Method of treating prostate cancer with GnRH antagonist

ABSTRACT

The invention provides methods and dosing regimens for safely and effectively treating androgen-dependent prostate cancer with a gonadotrophin releasing hormone (GnRH) antagonist without causing a testosterone spike and/or other side effect of GnRH agonist therapy such as a urinary tract infection, or an arthralgia-related or cardiovascular side effect. The present disclosure also provides for methods for treating prostate cancer in a patient with a history of at least one cardiovascular event, wherein administration of degarelix to the subject decreases the likelihood of developing or experiencing an additional cardiovascular event compared to treatment with a gonadotrophin releasing hormone (GnRH) agonist.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 15/205,108,filed Jul. 8, 2016, now U.S. Pat. No. 10,695,398, issued Jun. 30, 2020,which is a continuation of Ser. No. 13/458,330, filed Apr. 27, 2012, nowU.S. Pat. No. 9,415,085, issued Aug. 16, 2016; the entire contents ofall the referenced applications are incorporated herein by reference.

Prostate cancer is a leading cause of morbidity and mortality for men inthe industrialized world. The American Cancer Society estimates thatduring 2007 about 218,890 new cases of prostate cancer will have beendiagnosed in the United States alone. Prostate cancer is the secondleading cause of cancer death in American men, behind only lung cancer.However, while about 1 man in 6 will be diagnosed with prostate cancerduring his lifetime, only 1 man in 35 will actually die of it. TheAmerican Cancer Society estimates that 27,050 men in the United Stateswill die of prostate cancer in 2007. Prostate cancer accounts for about9% of cancer-related deaths in men.

While prostate cancer incidence rates rose dramatically in the late1980s, much of this increase is thought to reflect improvements indetection and diagnosis through widespread use of prostate-specificantigen (PSA) testing. Indeed, the incidence of prostate cancer has beendeclining since the early 1990s, and mortality rates for prostate cancerhave also declined since the early 1990s (see SEER Program and theNational Center for Health Statistics (seer.cancer.gov). More than 9 outof 10 prostate cancers are found in the local and regional stages (localmeans it is still confined to the prostate; regional means it has spreadfrom the prostate to nearby areas, but not to distant sites, such asbone). When compared to men of the same age and race who do not havecancer (relative survival), the 5-year relative survival rate for thesemen is nearly 100%, however the 5-year relative survival rate for menwhose prostate cancers have already spread to distant parts of the bodyat the time of diagnosis is only about 32%. It is estimated thatapproximately $8 billion is spent on prostate cancer treatment each yearin the United States alone (Cancer Trends Progress Report(progressreport.cancer.gov)).

The majority of prostate cancers are dependent on testosterone forgrowth, and the current medical management of advanced prostate cancerinvolves androgen deprivation, which may be achieved by bilateralorchiectomy or by administration of gonadotrophin releasing hormone(GnRH) receptor agonists. Removal of the testes (castration) was formany years the standard method of preventing the secretion of malehormones by the gonads as a means for reducing growth of prostatecancers. More recently, secretion of male hormones has been perturbed bychemical means by interfering with production of luteinizing hormone(LH), which regulates the synthesis of the androgens. Evidence fromrandomized studies strongly suggests that early endocrine therapy innon-metastatic, locally advanced disease with or without lymph nodemetastases is associated with a survival benefit (see Granfors et al.(1998) J. Urol. 159:2030-34; Messing et al. (1999) N. Eng. J. Med.341:1781-88; and (1997) Br. J. Urol. 79:235-46).

Gonadotrophin releasing hormone (GnRH) is a natural hormone produced bythe hypothalamus that interacts with a receptor in the pituitary tostimulate production of LH. To decrease LH production, agonists of theGnRH receptor (GnRH-R), such as leuprolide and goserelin, have beendeveloped. Such GnRH agonists are generally analogs of GnRH, thedecapeptide pyroGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂. Forexample, GnRH agonists having a D-isomer instead of Gly in the6-position have greater binding affinity/strength to the receptor andgreater biological potency than the native hormone; one example is the[D-Ala⁶]-GnRH (described in U.S. Pat. No. 4,072,668) having thefollowing formula: pGlu-His-Trp-Ser-Tyr-D-Ala-Leu-Arg-Pro-Gly-NH₂. SuchGnRH-R agonists initially act to stimulate LH release and only afterprolonged treatment act to desensitize GnRH-R such that LH is no longerproduced. The initial stimulation of LH production by the agonist leadsto an initial surge in the production of male sex hormones such that theinitial response to agonist therapy is aggravation, rather thanamelioration, of the patient's condition (e.g., tumor growth mayincrease). This phenomenon, known as the “testosterone surge” or “flarereaction,” can last for as long as two to four weeks. Additionally, eachsuccessive administration of the agonist can cause an additional smallLH surge (known as the “acute-on chronic” phenomenon) that can furtherworsen the condition. The testosterone surge stimulates prostate cancerand can lead to a worsening of current symptoms or appearance of newsymptoms such as spinal cord compression, bone pain and urethralobstruction (Thompson et al. (1990) J. Urol. 140:1479-80; Boccon-Gibodet al. (1986) Eur. Urol. 12: 400-402). One approach that has been takento avoid this problem has been to combine administration of a GnRH-Ragonist with an antiandrogen, such as flutamide, known as total androgenablation therapy (AAT). Hormonal therapy with an GnRH-R agonist incombination with an antiandrogen has been used as a pre-treatment priorto radical prostatectomy known as adjuvant therapy. The use ofantiandrogens, however, is associated with serious hepatic andgastrointestinal side effects.

Antagonists of the gonadotrophin releasing hormone receptor (GnRH-R)have been developed to overcome the “testosterone surge” or “flarereaction” associated with GnRH agonists. However, GnRH antagonistpeptides are frequently associated with the occurrence ofhistamine-releasing activity. This histamine-releasing activityrepresents a serious obstacle to the clinical use of such antagonistsbecause histamine release results in adverse side effects such as edemaand itching.

The search for improved GnRH antagonists has resulted in the making ofAntide, i.e. [Ac-D-2NaI¹, D-4CIPhe², D-3PaI³, Lys(Nic)⁵, D-Lys(Nic)⁶,ILys⁸, D-Ala¹⁰]-GnRH; and Cetrorelix, i.e. [Ac-D-2NaI¹, D-4CIPhe²,D-3PaI³, D-Cit⁶, D-Ala¹⁰]-GnRH. U.S. Pat. No. 5,516,887 describes GnRHantagonists which are said to be more effective than Antide insuppressing plasma testosterone, e.g. [Ac-D-2NaI¹, D-4CIPhe², D-3PaI³,D-N^(ε)-carbamoyl Lys⁶, Ilys⁸, D-Ala¹⁰]-GnRH, which is referred to asAntarelix. Furthermore, U.S. Pat. No. 5,296,468 discloses the design andsynthesis of a number of GnRH antagonists wherein the side chains ofselected residues are reacted to create cyanoguanidino moieties, some ofwhich subsequently spontaneously convert to a desired heterocycle, e.g.a 3-amino-1,2,4-triazole(atz). Such cyanoguanidino moieties are builtupon the omega-amino group in an amino acid side chain, such as lysine,ornithine, 4-amino phenylalanine (4Aph) or an extended chain versionthereof, such as 4-amino homophenylalanine (4Ahp). GnRH antagonistshaving such significantly modified or unnatural amino acids in the 5-and 6-positions exhibit good biological potency, and those built uponAph are generally considered to be particularly potent. One that isespecially useful is Azaline B, i.e. [Ac-D-2NaI¹, D-4CIPhe², D-3PaI³,4Aph(atz)⁵, D-4Aph(atz)⁶, ILys⁸, D-Ala¹⁰]-GnRH. U.S. Pat. No. 5,506,207discloses biopotent GnRH antagonists with acylated, amino-substitutedphenylalanine side chains of residues in the 5- and 6-positions; onesuch decapeptide is Acyline, i.e. [Ac-D-2NaI¹, D-4CIPhe², D-3PaI³,4Aph(Ac)⁵, D-4Aph(Ac)⁶, ILys⁸, D-Ala¹⁰]-GnRH. Despite the attractiveproperties of this group of GnRH antagonists, the search has continuedfor still further improved GnRH antagonists, particularly those whichexhibit long duration of biological action. It can frequently beimportant that a peptide analog should exhibit a long duration ofactivity with respect to LH secretion, a property which may be enhancedby the peptide's resistance to proteolytic enzyme degradation in thebody for both short-term and long-term treatment indications. Inaddition, to facilitate administration of these compounds to mammals,particularly humans, without significant gelling, it is consideredextremely advantageous for such GnRH antagonistic decapeptides to havehigh solubility in water at normal physiologic pH, i.e. about pH 5 toabout pH 7.4.

While the use of both GnRH agonist and antagonists in androgendeprivation therapy to treat prostate cancer has yielded promisingresults, there are concerns about the relative safety of the availabledrugs. For example, the GnRH abarelix was found to carry a risk ofserious allergic reactions, including anaphylaxis with hypotension andsyncope, and was also found to lose efficacy over the course oftreatment in some cases. Indeed, Abarelix™ (Plenaxis™ in the U.S.) waseventually approved, but only for patients with advanced prostatecancer, and was eventually withdrawn from the market in 2005 forcommercial reasons apparently related to these problems. Furthermore,while prostate cancer-specific mortality has been decreasing, there hasbeen little overall effect on mortality in this group, suggesting thepossibility of an increased risk of death from nonprostate cancerrelated causes. In particular, it has been suggested that certainandrogen deprivation therapies could adversely affect cardiovascularhealth (see Yannucci et al. (2006) J. Urology 176:520-525; and Etzioniet al. (1999) J. Natl. Canc. Inst. 91:1033).

Androgen deprivation therapy (ADT) induced by GnRH agonists is gainingincreased use in not only metastatic but also in locally advancedprostate cancer (PCa) patients. (see Gilbert et al. (2011) Urol. Oncol.29:647-53; and Shahinian et al. (2005) Cancer 103:1615-1624.) Withincreasing experience with the use of agonists in earlier stage disease,concerns have emerged about the relative importance of a variety ofadverse effects, including osteoporosis, diabetes, and as discussedabove, certain cardiovascular (CV) events. (Saylor et al. (2010) J.Natl. Compr. Canc. Netw. 8:211-23.) While the increased risk of diabetesand osteoporosis (both driven by androgen deprivation) is a consistentfinding across different studies and forms of ADT (Taylor et al (2009)Cancer 115:2388-99), the increased risk of CV events posed by GnRHagonists is still a subject of debate, even after addition of thissafety issue to the label of these drugs. Variation in study designsincluding differences in study populations, differences in the referencegroup, the number and type of CV events analyzed, and the follow-up timeare likely contributors to the apparent controversies (Alibhai et al.(2009) J. Clin. Oncol. 27:3452-8; Razzak (2012) Nat. Rev. Urol. 9:61;Levine et al. (2010) Circulation 121:833-40; and Van Poppel et al.(2011) 3:49-55). Another limitation of obtaining clarity has been thelack of a plausible hypothesis concerning the mechanism of actiondriving the rise of CV complications. Nevertheless, there are somepreliminary observations suggesting that advanced age and history of CVevents increase the probability of capturing the CV harm of GnRHagonists (Keating et al. (2006) J. Clin. Oncol. 24:4448-56; Keating etal. (2009) J. Natl. Cancer Inst. 1-8; Saigal et al. (2007) Cancer110:1493-500; Hayes et al. (2010) BJU Int. 106:979-85; and Nanda et al.(2009) JAMA 302:866-73).

The fact that GnRH agonists remain by far the most extensively used formof medical ADT explains why there is a tendency to use GnRH agonists andADT as synonyms. Only few investigators have raised the notion that theCV harm of GnRH agonists could also be mediated by triggering of GnRHreceptors instead of the effects of testosterone deprivation (Dong etal. (2011) J. Neuroendocrinol 23:456-63). This line of thinking comesfrom reports suggesting that stand-alone antiandrogens do not seem toconfer CV harm (Keating et al. (2009) J. Natl. Cancer Inst. 1-8 andRobinson et al. (2012) Int. J. Cancer 130:478-87). Degarelix, a GnRHantagonist opens a unique possibility to obtain further insights intothe role of GnRH receptors. A previous analysis on 1704degarelix-treated PCa patients participating in clinical trials,demonstrated comparable CV event rates before and after treatmentinitiation (Smith et al. (2011) J. Urol. 186:1835-42), suggesting no CVharm. However, ultimate answers to whether the CV safety profile ofantagonist is distinct from agonists can only come from directcomparison of these classes in randomized clinical trials.

Accordingly, new therapeutic regiments for prostate cancer are neededthat are free of both the adverse consequences of the GnRH agonisttestosterone spike, as well as the undesirable side effects of availableGnRH antagonist therapies. It is also beneficial to conduct a directcomparison of antagonists and agonists in randomized clinical trials todetermine whether the cardiovascular safety profile of antagonist isdistinct from agonists.

SUMMARY OF THE INVENTION

Applicants have found that a relatively low dose of degarelix GnRHantagonist, delivered about once every 28 days (e.g., monthly), cansafely and rapidly suppress testosterone levels to therapeutic levels inprostate cancer patients, without causing a testosterone spike and withan appreciably diminished risk of causing an undesirable side effectassociated with androgen deprivation therapy such as a cardiac disorder,arthralgia, and/or a urinary tract infection.

In one aspect, the invention provides a method of treating prostatecancer in a subject with a reduced likelihood of causing a testosteronespike or other side effect of a gonadotrophin releasing hormone (GnRH)agonist therapy. The method includes administering an initial dose ofabout 240 mg of degarelix to the subject; and administering amaintenance dose of about 80 mg of degarelix to the subject once everyapproximately 28 days thereafter, and thereby treating prostate cancerin the subject with a reduced likelihood of causing a testosterone spikeor other GnRH agonist side effect.

In a further aspect, the invention provides a method of treatingprostate cancer in a subject with a reduced likelihood of causing atestosterone spike or other side effect of a gonadotrophin releasinghormone (GnRH) agonist therapy. The method includes administering aninitial dose of 160-320 mg of degarelix to the subject; andadministering a maintenance dose of 60-160 mg of degarelix to thesubject once every 20-36 days thereafter, and thereby treating prostatecancer in the subject with a reduced likelihood of causing atestosterone spike or other GnRH agonist side effect.

In certain embodiments of these methods of the invention, themaintenance dose is administered monthly. In further embodiments, thetreated subject has a decreased likelihood of developing or experiencingan undesirable side effect during treatment compared to treatment withthe gonadotrophin releasing hormone (GnRH) agonist leuprolide. Inparticular embodiments, the treated subject has a decreased likelihoodof developing or experiencing a cardiovascular side effect such as amyocardial infarction, chest pain, a cardiac murmur or a vascular sideeffect (e.g., deep vein thrombosis (DVT)) during treatment compared totreatment with the gonadotrophin releasing hormone (GnRH) agonistleuprolide. In further embodiments, the methods provide the treatedsubject with a decreased likelihood of developing a side effect selectedfrom the group consisting of a cardiac arrhythmia, a coronary arterydisorder, and a cardiac disorder. In particularly useful embodiments,the treated subject has a body mass index (BMI) of less than 30 kg/m²,particularly a BMI of less than 25 kg/m². In further useful embodimentsthe treated subject has a cholesterol level of greater than or equal to4 mmol/L (155 mg/dL).

In further embodiments, the methods of the invention are used to treat asubject who is at risk for cardiovascular disease. In particularlyuseful embodiments, the methods of the invention further include thestep of identifying a prostate cancer subject who is also at risk forcardiovascular disease for treatment by the method.

In still further embodiments, the treated subject has a decreasedlikelihood of developing or experiencing an increase in arthralgiaand/or musculoskeletal stiffness during treatment compared to treatmentwith the gonadotrophin releasing hormone (GnRH) agonist leuprolide. Inparticularly useful embodiments thereof, the treated subject has locallyadvanced prostate cancer and/or is less than 65 years old.

In further embodiments, the treated subject has a decreased likelihoodof developing a musculoskeletal disorder and/or a connective tissuedisorder during treatment compared to treatment with the gonadotrophinreleasing hormone (GnRH) agonist leuprolide. In particular embodiments,the musculoskeletal disorder and/or a connective tissue disorder isarthralgia. In other embodiments, the musculoskeletal disorder and/or aconnective tissue disorder is musculoskeletal stiffness.

In still further embodiments of these methods of the invention, thetreated subject has a decreased likelihood of developing noninfectivecystitis during treatment compared to treatment with the gonadotrophinreleasing hormone (GnRH) agonist leuprolide.

In another embodiment, the treated subject has a decreased likelihood ofdeveloping a urinary or renal system disorder compared to treatment withthe gonadotrophin releasing hormone (GnRH) agonist leuprolide. Incertain embodiments, the urinary or renal system disorder is a urinarytract infection. In particularly useful embodiments thereof, the treatedsubject has locally advanced prostate cancer. In another embodiment, theurinary or renal system disorder is an increase in urinary retention. Instill another embodiment, the urinary or renal system disorder is anoninfective cystitis.

In still other embodiments, the treated subject has a decreasedlikelihood of developing erectile dysfunction during treatment comparedto treatment with the gonadotrophin releasing hormone (GnRH) agonistleuprolide. In other embodiments, the treated subject has a decreasedlikelihood of decreased libido during treatment compared to treatmentwith the gonadotrophin releasing hormone (GnRH) agonist leuprolide.

In particular embodiments of the above methods of the invention, thetreated subject has at least about a 95% likelihood of maintaining atherapeutically low serum testosterone level of less than or equal to0.5 ng/mL by day 28 of treatment. In certain embodiments, the treatedsubject has at least about a 95% likelihood of maintaining atherapeutically low serum testosterone level of less than or equal to0.5 ng/mL from day 28 through day 364 of treatment. In still furtherembodiments, the treated subject has at least about a 30% decrease inprostate specific antigen (PSA) by day 14 of treatment. In particularembodiments, the treated subject has at least about a 50% decrease inprostate specific antigen (PSA) by day 14 of treatment. In furtherembodiments, the treated subject has at least about a 60% decrease inprostate specific antigen (PSA) by day 28 of treatment. In still furtherembodiments, the treated subject has at least about a 75% decrease inprostate specific antigen (PSA) by day 28 of treatment.

In further embodiments of the method of the invention, the treatedsubject has at least about an 80% (e.g., a 95%) likelihood ofmaintaining a low prostate specific antigen (PSA) level of less thanabout 5 ng/mL during treatment.

In further embodiments of the method of the invention, the treatedsubject has locally advanced prostate cancer and has at least about a40% decrease in PSA by day 14 of treatment.

In still further embodiments, the treated subject has metastaticprostate cancer and has at least about a 60% decrease in PSA by day 14of treatment.

In particular embodiments of the above methods of the invention, thetreated subject has a body mass index of less than 30 kg/m² (especiallyless than 25 kg/m²).

In another aspect, the invention provides methods of treating prostatecancer in a subject at risk for a cardiovascular disease or disorder byadministering a therapeutically effective dose of degarelix to thesubject with prostate cancer who is at risk for a cardiovascular diseaseor disorder. In particular embodiments, the therapeutically effectivedose includes an initial starting dose of 160 to 320 mg of degarelix,and a monthly maintenance dose of 60 to 160 mg of degarelix. In furtherembodiments, the therapeutically effective dose of degarelix includes amaintenance dose of about 80 mg of degarelix once every approximately 28days of treatment. In certain embodiments thereof, the therapeuticallyeffective dose of degarelix further includes a single initial dose ofabout 240 mg of degarelix at the start of treatment.

In particular embodiments, the subject treated has been identified to beat risk of a specific cardiovascular disease or disorder such as cardiacmurmur, atrioventricular blockage, and/or myocardial ischemia.

In further embodiments, the treated subject possesses an indicator ofincreased risk for cardiovascular disease, e.g. high blood pressure,high low-density lipoprotein cholesterol, low high-density lipoproteincholesterol, high serum glucose and/or a habitual smoking habit. Inparticular embodiments, the treated subject has high blood pressure ofgreater than or equal to 130 over 85 mm Hg. In further embodiments, thetreated subject smokes cigarettes daily. In still further embodiments,the treated subject has an elevated level of low-density lipoproteincholesterol of greater than or equal to about 160 mg/dl. In furtherembodiments, the treated subject has a low level of high-densitylipoprotein cholesterol of less than 35 mg/dl. In other embodiments, thetreated subject has an elevated fasting glucose level of greater thanabout 120 mg/dL.

In still other particularly useful embodiments, the treated subjectpossesses an indicator of increased risk for cardiovascular disease suchas high serum C-reactive protein (CRP), high serum homocysteine, highserum fibrinogen, and/or high serum lipoprotein(a) (Lp(a)). Inparticular embodiments, the treated subject has an elevated level ofC-reactive protein of greater than 3 mg/dL. In other embodiments, thetreated subject has an elevated level of serum homocysteine of greaterthan 30 μmol/L. In further embodiments, the treated subject has anelevated level of serum fibrinogen of greater than 7.0 g/L. In stillfurther embodiments, the treated subject has an elevated level of serumLp(a) of greater than 30 mg/dL.

In certain embodiments, the treated subject has a body mass index ofless than 30 kg/m² (particularly less than 25 kg/m²).

In further embodiments, the treated subject has a decreased likelihood,compared to treatment with the gonadotrophin releasing hormone (GnRH)agonist leuprolide, of developing a cardiovascular side effect such ascardiac arrhythmia, coronary artery disorder, and/or a cardiac disorder.In particular embodiments thereof, the treated subject has a body massindex (BMI) of less than 30 kg/m² (especially less than 25 kg/m²). Inother embodiments, the treated subject has a cholesterol level ofgreater than or equal to 4 mmol/L (155 mg/dL).

In still another aspect, the invention provides a method of treatingprostate cancer in a subject at risk for a cardiovascular disease ordisorder by first identifying a suitable subject with prostate cancerthat is also at risk for a cardiovascular disease or disorder. Thesuitable subject with cardiovascular disease risk is then administeredan initial dose of about 240 mg of degarelix, followed by a maintenancedose of about 80 mg of degarelix once every approximately 28 daysthereafter, thereby treating prostate cancer in the subject at risk fora cardiovascular disease or disorder. In certain embodiments, themaintenance dose of degarelix is administered monthly.

In a further aspect, the invention provides a method of treatingprostate cancer in a subject at risk for a cardiovascular disease ordisorder by first identifying a suitable subject with prostate cancerand at risk for a cardiovascular disease or disorder. The suitablesubject with cardiovascular disease risk is then administered an initialdose of 160-320 mg of degarelix, followed by a maintenance dose of60-160 mg of degarelix delivered once every approximately 28 daysthereafter, thereby treating prostate cancer in the subject at risk fora cardiovascular disease or disorder with a reduced likelihood ofcausing a testosterone spike or other GnRH agonist side-effect. Incertain embodiments, the maintenance dose of degarelix is administeredmonthly. In particular embodiments of this aspect, the treated subjecthas a body mass index of less than 30 kg/m² (particularly a BMI of lessthan 25 kg/m²). In further embodiments, the treated subject is at riskof a cardiovascular disease or disorder, such as a cardiac murmur, anatrioventricular blockage, and/or myocardial ischemia. In still otherembodiments, the treated subject possesses an indicator of increasedrisk for cardiovascular disease. In further particular embodiments, thetreated subject possesses an indicator of increased risk forcardiovascular disease, e.g. high blood pressure, high low-densitylipoprotein cholesterol, low high-density lipoprotein cholesterol, highserum glucose and/or a habitual smoking habit. In particularembodiments, the treated subject has high blood pressure of greater thanor equal to 130 over 85 mm Hg. In further embodiments, the treatedsubject smokes cigarettes daily. In still further embodiments, thetreated subject has an elevated level of low-density lipoproteincholesterol of greater than or equal to about 160 mg/dL. In furtherembodiments, the treated subject has a low level of high-densitylipoprotein cholesterol of less than 35 mg/dl. In other embodiments, thetreated subject has an elevated fasting glucose level of greater thanabout 120 mg/dL.

In still other embodiments, the treated subject possesses an indicatorof increased risk for cardiovascular disease such as high serumC-reactive protein (CRP), high serum homocysteine, high serumfibrinogen, and/or high serum lipoprotein(a) (Lp(a)). In particularembodiments, the treated subject has an elevated level of C-reactiveprotein of greater than 3 mg/dL. In other embodiments, the treatedsubject has an elevated level of serum homocysteine of greater than 30μmol/L. In further embodiments, the treated subject has an elevatedlevel of serum fibrinogen of greater than 7.0 g/L. In still furtherembodiments, the treated subject has an elevated level of serum Lp(a) ofgreater than 30 mg/dL. In other embodiments, the treated subject has adecreased likelihood, when compared to treatment with the gonadotrophinreleasing hormone (GnRH) agonist leuprolide, of developing acardiovascular side effect such as a cardiac arrhythmia, a coronaryartery disorder, and/or a cardiac disorder. In certain embodimentsthereof, the treated subject has a body mass index of less than 30 kg/m²(particularly less than 25 kg/m²).

In yet another aspect, the invention provides a method of treatingprostate cancer in a preferred subject by identifying a subject withprostate cancer having a body mass index of less than about 25 kg/m².The preferred subject thus identified is administered a single initialdose of 160-320 mg of degarelix, followed by monthly doses of 60-160 mgof degarelix administered once every 20-36 days thereafter. In certainembodiments, the treated subject has a decreased likelihood, whencompared to treatment with the gonadotrophin releasing hormone (GnRH)agonist leuprolide, of developing a cardiovascular side effect such as acardiac arrhythmia, a coronary artery disorder, and/or a cardiacdisorder. In particular embodiments, the initial dose of degarelix isabout 240 mg, and the maintenance dose of degarelix is about 80 mgadministered monthly. In further particular embodiments, the preferredsubject has a cholesterol level of greater than or equal to 4 mmol/L(155 mg/dL).

In further embodiments, the methods of treatment of the invention may bewith, or associated with, a reduced incidence or likelihood of one ormore of cardiovascular and/or vascular side effects (for example withreduced incidence and/or likelihood of one or more of myocardialinfarction, chest pain, chest pain development, cardiac murmur, cardiacmurmur development, myocardial ischemia, atrioventricular blockage, deepvein thrombosis (DVT), cardiac arrhythmia, coronary artery disorder,and/or cardiac disorder), musculoskeletal disorder (for examplearthralgia and/or musculoskeletal stiffness), connective tissuedisorder, urinary and/or renal system disorder.

In an additional embodiment, the present disclosure provides a method oftreating prostate cancer in a subject who has had at least onecardiovascular event, wherein administration of degarelix to the subjectdecreases the likelihood of developing or experiencing an additionalcardiovascular event compared to treatment with a gonadotrophinreleasing hormone (GnRH) agonist.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a depiction of the chemical structure of degarelix.

FIG. 2 is a graphical representation of the effect of degarelix 240mg/80 mg dosing on plasma testosterone from day 0 to day 364 oftreatment.

FIG. 3 is a graphical representation comparing the effect of degarelix240 mg/80 mg dosing with the effect of Lupron 7.5 mg dosing on thepercentage change in plasma testosterone from day 0 to day 28 oftreatment.

FIG. 4 is a graphical representation comparing the effect of degarelix240 mg/160 mg and degarelix 240 mg/80 mg dosing with the effect ofLupron 7.5 mg dosing on the median levels of luteinizing hormone (LH)over time from day 0 to day 364 of treatment.

FIG. 5 is a graphical representation comparing the effect of degarelix240 mg/160 mg and degarelix 240 mg/80 mg dosing with the effect ofLupron 7.5 mg dosing on the median levels of follicle stimulatinghormone (FSH) over time from day 0 to day 364 of treatment.

FIG. 6 is a graphical representation comparing the effect of degarelix240 mg/80 mg dosing with the effect of Lupron 7.5 mg dosing on prostatespecific antigen (PSA) levels from day 0 to day 56 of treatment.

FIG. 7 is a graphical representation of the six randomized clinicaltrials included in Example 2, which illustrate the number of patientsand doses of the drugs utilized for androgen deprivation therapy andtime periods of these trials.

FIG. 8 is a graphical representation showing the median (±interquartilerange) of serum testosterone level during androgen deprivation therapywith either degarelix or a standard GnRH agonist of Example 2.

FIGS. 9 A-D are 1-Kaplan-Meier plots of time to first-reportedcardiovascular event in prostate cancer patients with and without ahistory of cardiovascular events in patients receiving treatment withdegarelix versus agonist of Example 2.

DETAILED DESCRIPTION OF THE INVENTION

Particular aspects of the invention are described in greater detailbelow. The patent and scientific literature referred to herein arehereby incorporated by reference.

General

In general, the invention provides methods of treating prostate cancerwith degarelix GnRH antagonist using a dosing regimen that results inoptimal efficacy, and reduced serious side-effects, particularly incertain patient subgroups, compared to other androgen deprivationtherapies, particularly GnRH agonist therapies such as leuprolide.

The relative efficacy and safety (including adverse side effects) of theGnRH agonist therapy leuprolide (also leuprorelin or LUPRON) is known inthe art (see e.g., Persad (2002) Int. J. Clin. Pract. 56:389-96; Wilsonet al. (2007) Expert Opin. Invest. Drugs 16:1851-63; and Berges et al.(2006) Curr. Med. Res. Opin. 22:649-55). In addition, the relativeefficacy and safety of the GnRH antagonist therapy abarelix (PLENAXIS)has also been reported (see, e.g., Mongiat-Artus et al. (2004) ExpertOpin. Pharmacother. 5:2171-9; and Debruyne et al. (2006) Future Oncol.2:677-96). A review of the basic methods for conducting and analyzingthe type of controlled clinical studies described herein, includinganalyses of safety, efficacy and selective advantages to certain patientsubpopulations, is available (see Spilker (1991) Guide to ClinicalTrials Raven Press, New York; and Spilker (1996) Quality of Life andPharmacoeconomics in Clinical Trials Lippincott—Raven Publishers NewYork).

Definitions

The singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise.

As used herein, the term “ADR” refers to an adverse drug reaction, andthe term “AE” refers to an “adverse event.”

The terms “approximately” and “about” mean to be nearly the same as areferenced number or value. As used herein, the terms “approximately”and “about” should be generally understood to encompass ±10% a specifiedamount, frequency or value.

The term “agonist” as used herein, is meant to refer to an agent thatmimics or up-regulates (e.g., potentiates or supplements) thebioactivity of a protein. An agonist can be a wild-type protein orderivative thereof having at least one bioactivity of the wild-typeprotein.

“Antagonist” as used herein is meant to refer to an agent thatdown-regulates (e.g., suppresses or inhibits) at least one bioactivityof a protein.

As used herein, the term “arthralgia” refers to pain in one or morejoints, which may occur as a symptom of injury, infection, illnesses—inparticular arthritis—or an allergic reaction to medication. Indistinguishing the term “arthralgia” from the term “arthritis” it shouldbe noted that “arthralgia” specifically refers to non-inflammatoryconditions, and the term “arthritis” should be used when the conditionis an inflammatory condition.

The term “body mass index” (BMI) refers to a statistical measure of theweight of a person scaled according to height, which is an approximatingmeasure of the relative percentages of fat and muscle mass in the humanbody. BMI is defined as the individual's body weight divided by thesquare of their height, and the formulas used in medicine produce a unitof measure of kg/m².

The term “CI” refers to a statistical confidence interval and the term“HR” refers to hazard rate(s).

The term “CV” refers to a cardiovascular.

The term “cardiovascular” as used herein refers to conditions involvingthe heart and/or blood vessels.

The term “cardiac arrhythmia” as used herein is any of a group ofconditions in which the electrical activity of the heart is irregular oris faster or slower than normal.

As used herein, the terms “coronary artery disorder” or “coronary arterydisease” refers to a condition (such as sclerosis or thrombosis) thatreduces the blood flow through the coronary arteries to the heartmuscle.

The term “cardiac disorder” as used herein refers to any of a number ofabnormal organic conditions affecting the heart including coronary heartdisease, heart attack, cardiovascular disease, pulmonary heart diseaseand high blood pressure.

The term “deep-vein thrombosis” (also known as deep-venous thrombosis orDVT) is the formation of a blood clot (“thrombus”) in a deep vein.Deep-vein thrombosis commonly affects the leg veins, such as the femoralvein or the popliteal vein or the deep veins of the pelvis. Occasionallythe veins of the arm are affected (known as Paget-Schrötter disease).Thrombophlebitis is the more general class of pathologies of this kind.There is a significant risk of the thrombus embolizing and traveling tothe lungs causing a pulmonary embolism.

The term “ECG” refers to an electrocardiogram.

The term “MedDRA” refers to the Medical dictionary for regulatoryactivities.

The term “myocardial infarction” refers to an infarction of themyocardium that results typically from coronary occlusion, which may bemarked by sudden chest pain, shortness of breath, nausea, and loss ofconsciousness, and sometimes death. An “infarction” refers to theprocess of forming an infarct, which is an area of necrosis in a tissueor organ resulting from obstruction of the local circulation by athrombus or embolus.

“Male sexual dysfunction” includes impotence, loss of libido, anderectile dysfunction. “Erectile dysfunction” is a disorder involving thefailure of a male mammal to achieve erection, ejaculation, or both.

The term “prostate cancer” refers to any cancer of the prostate gland inwhich cells of the prostate mutate and begin to multiply out of control.The term “prostate cancer” includes early stage, localized, cancer ofthe prostate gland; later stage, locally advanced cancer of the prostategland; and later stage metastatic cancer of the prostate gland (in whichthe cancer cells spread (metastasize) from the prostate to other partsof the body, especially the bones and lymph nodes).

The term “prostate-specific antigen” or “PSA” refers to a proteinproduced by the cells of the prostate gland that is present in smallquantities in the serum of normal men, but is often elevated in thepresence of prostate cancer and in other prostate disorders. A bloodtest to measure PSA is the most effective test currently available forthe early detection of prostate cancer. Higher than normal levels of PSAare associated with both localized and metastatic prostate cancer (CaP).

The term “PD” refers to pharmacodynamic, and the term “PK” refers topharmacokinetic.

The term “PT” refers to a preferred term.

The term “SAE” refers to a serious adverse event”.

The term “SD” refers to standard deviation.

The term “SOC” refers to a system organ class.

The term “SUSAR” refers to a suspected, unexpected serious adversereaction.

A “subject” or “patient” is a male mammal, more preferably a human male.Non-human male mammals include, but are not limited to, farm animals,sport animals, and pets.

A “urinary tract infection” (UTI) is a bacterial infection that affectsany part of the urinary tract, which is the tract through which urinepasses and includes the renal tubules and renal pelvis of the kidney,the ureters, the bladder, and the urethra. The most common type of UTIis a bladder infection which is also often called cystitis. Another kindof UTI is a kidney infection, known as pyelonephritis, which is a moreserious condition.

Degarelix and Related Pharmaceutical Formulations

Degarelix is a potent GnRH antagonist that is an analog of the GnRHdecapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly—NH₂) incorporatingp-ureido-phenylalanines at positions 5 and 6 (Jiang et al. (2001) J.Med. Chem. 44:453-67). It is indicated for treatment of patients withprostate cancer in whom androgen deprivation is warranted (includingpatients with rising PSA levels after having already undergoneprostatectomy or radiotherapy).

Degarelix is a selective GnRH receptor antagonist (blocker) thatcompetitively and reversibly binds to the pituitary GnRH receptors,thereby rapidly reducing the release of gonadotrophins and consequentlytestosterone (T). Prostate cancer is sensitive to testosteronedeprivation, a mainstay principle in the treatment of hormone-sensitiveprostate cancer. Unlike GnRH agonists, GnRH receptor blockers do notinduce a luteinizing hormone (LH) surge with subsequent testosteronesurge/tumor stimulation and potential symptomatic flare after theinitiation of treatment.

Degarelix is available as a powder for injectable formulation and asolvent for reconstitution of the powder. The powder for injectableformulation is a lyophilisate containing degarelix and mannitol, and thesolvent consists of water for injection provided in 6 mL vials.

The active ingredient degarelix is a synthetic linear decapeptide amidecontaining seven unnatural amino acids, five of which are D-amino acids.The drug substance is an acetate salt, but the active moiety of thesubstance is degarelix as the free base. The acetate salt of degarelixis a white to off-white amorphous powder of low density as obtainedafter lyophilisation. The chemical name is D-Alaninamide,N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo-4-pyrimidinyl]carbonyl]amino]-Lphenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl-Lleucyl-N6-(1-methylethyl)-L-lysyl-L-prolyl. It has an empirical formulaof C₈₂H₁₀₃N₁₈O₁₆Cl and a molecular weight of 1,632.3 Da.

The chemical structure is of degarelix is shown in FIG. 1 and may alsobe represented by the formula:Ac-D-NaI-D-Cpa-D-PaI-Ser-Aph(Hor)-D-Aph(Cbm)-Leu-Lys(iPr)—Pro-D-Ala-NH₂

Degarelix is one member of a family of GnRH antagonists, described infurther detail in U.S. Pat. No. 5,925,730 and EP 1003774 that carrymodifications in positions 5 and 6 and have potent GnRH receptor bindingactivity as well as the particularly advantageous property of longduration of bioactivity. Related GnRH antagonists are known in the artand described, e.g., in U.S. Pat. Nos. 5,821,230 and 6,214,798.

Administration and Dosing

A preferred dosing regimen for treating adult males with prostate canceris a single 240 mg starting dose of degarelix administered as twosubcutaneous injections of 120 mg; and followed by monthly maintenancedoses of 80 mg of degarelix administered as a single subcutaneousinjection beginning approximately one month after the initial startingdose.

Degarelix may be formulated for administration subcutaneously, asopposed to intravenously, generally in the abdominal region, asdescribed in further detail below. As with other drugs administered bysubcutaneous injection, the injection site may vary periodically toadapt the treatment to injection site discomfort. In general, injectionsshould be given in areas where the patient will not be exposed topressure, e.g. not close to waistband or belt and not close to the ribs.

Administration of degarelix by subcutaneous or intramuscular injectionworks well, but daily injections are generally not acceptable and so adepot formulation of degarelix may be utilized as describe in furtherdetail in WO 03/006049 and U.S. Pub. Nos. 20050245455 and 20040038903.

Briefly, subcutaneous administration of degarelix may be conducted usinga depot technology in which the peptide is released from a biodegradablepolymer matrix over a period of (typically) one to three months.Degarelix and related GnRH antagonist peptides as described in WO03/006049 and U.S. Pub. Nos. 2005/0245455 and 2004/0038903, have a highaffinity for the GnRH receptor and are much more soluble in water thanother GnRH analogues. Degarelix and these related GnRH antagonists arecapable of forming a gel after subcutaneous injection, and this gel canact as a depot from which the peptide is released over a period of weeksor even months.

A key variable for formation of an effective degarelix depot is theconcentration of the solution in combination with the amount ofsubstance administered per se. The concentration of the must be within afunctional range. If the formulation is too dilute then no depot isformed and the long duration of action is lost, regardless of the amountof drug substance given. If the formulation is too concentrated then gelformation will occur before the drug can be administered. Effectivedepot-forming formulations of degarelix generally have a concentrationof not less than 5 mg/mL degarelix, e.g. 5 to 40 mg/mL of degarelix.Accordingly, the dosing regimen for degarelix may be administered as aninitial, starting dose of 240 mg administered as 6 mL of about 40 mg/mL(e.g., 2 injections of about 3 mL (e.g., 3.2 mL)) degarelix formulation,followed by monthly maintenance doses of 80 mg administered as a singleinjection of 4 mL of about 20 mg/mL degarelix formulation.Alternatively, monthly maintenance doses of 160 mg may be utilized, e.g.by administering 4 mL of about 40 mg/mL degarelix every month.

Thus, degarelix may be provided as a powder for reconstitution (with asolvent) as a solution for injection (e.g. subcutaneous injection, e.g.to form a depot as described above). The powder may be provided as alyophilisate containing degarelix (e.g. as acetate) and mannitol. Asuitable solvent is water (e.g., water for injection, or WFI). Forexample, degarelix may be provided in a vial containing 120 mg degarelix(acetate) for reconstitution with about 3 mL WFI (e.g., 3.2 mL) suchthat each mL of solution contains about 40 mg degarelix. In anotherexample, degarelix may be provided in a vial containing 80 mg degarelix(acetate). After reconstitution with about 4 mL WFI each mL solutioncontains about 20 mg degarelix.

The reconstituted formulation should be a clear liquid, free ofundissolved matter. A single dose of 240 mg degarelix, followed by amonthly maintenance dose of 80 mg, rapidly causes a decrease in theconcentrations of the luteinizing hormone (LH), follicle stimulatinghormone (FSH) and subsequently testosterone. The plasma concentration ofdihydrotestosterone (DHT) decreases in a similar manner to testosterone.

Degarelix is effective in achieving and maintaining testosteronesuppression well below medical castration level of 0.5 ng/mL. Asdescribed below in further detail, maintenance monthly dosing of 80 mgresulted in sustained testosterone suppression in 97% of patients for atleast one year and median testosterone levels after one year oftreatment were 0.087 ng/mL.

The relevant pharmacokinetic parameters for degarelix evaluated inprostate cancer patients are summarized in Table 1, below. Mediandegarelix trough concentrations in the maintenance phase with 80 mg at aconcentration of 20 mg/mL was 10.9 ng/mL.

TABLE 1 Declarelix pharmacokinetic parameters after subcutaneousadministration of 240 mg at a concentration of 40 mg/mL Pharmacokineticdegarelix parameter 240 mg Cmax (ng/mL) 53.4 Tmax (days) 1.4 T½ (days)43 AUC (day · ng/mL) 1240

Following subcutaneous administration of 240 mg degarelix (6 mL at aconcentration of about 40 mg/mL) to prostate cancer patients, degarelixis eliminated in a biphasic fashion, with a median terminal half-life ofapproximately 43 days. The long half-life after subcutaneousadministration is a consequence of a very slow release of degarelix fromthe depot formed at the injection site(s). The pharmacokinetic behaviorof the drug is strongly influenced by its concentration in the injectionformulation.

The resulting distribution volume in healthy elderly men isapproximately 1 L/kg. Plasma protein binding is estimated to beapproximately 90%.

Degarelix is subject to common peptidic degradation during the passageof the hepato-biliary system and is mainly excreted as peptide fragmentsin the feces. No significant metabolites were detected in plasma samplesafter subcutaneous administration. In vitro studies have shown thatdegarelix is not a substrate for the human CYP450 system. Therefore,clinically significant pharmacokinetic interactions with other drugs areunlikely to occur.

In healthy men, approximately 20% of a given dose of degarelix wasrenally excreted, suggesting that approximately 80% is excreted via thehepato-biliary system in humans. The clearance in healthy elderly men is35-50 mL/hr/kg.

Adverse Events (Side Effects)

Degarelix has been found to be generally well tolerated in clinicaltrials. The most commonly observed adverse reactions during degarelixtherapy were due to the expected physiological effects of testosteronesuppression, mainly hot flushes and increased weight, and injection siterelated adverse events, mainly injection site pain and injection siteerythema.

In the confirmatory active-controlled clinical trial comparing degarelixsubcutaneous (s.c.) with leuprolide intramuscular (i.m.) for 12 monthsof treatment of patients with prostate cancer, the most frequentlyreported side effects were adverse events occurring at the injectionsite including pain (28%), erythema (17%), swelling (6%), induration(4%) and nodule (3%). These adverse events were mostly transient, ofmild to moderate intensity and occurred primarily with the starting doseand led to very few discontinuations (<1%). The majority of injectionsite adverse events did not require any treatment. Of the reportedevents 20% were ameliorated by the patients receiving treatment withover the counter (OTC) remedies such as analgesics or cold packs. Inaddition, there were a number of other frequent adverse events includingweight increase, fatigue, chills, hot flush, hypertension, back pain,arthralgia, and urinary tract infection, as summarized in Table 2 below.

TABLE 2 Comparison of Most Frequent Adverse Events for deqarelix versusleuprolide Treatment degarelix leuprolide 240/80 mg (s.c.) 7.5 mg (i.m.)N = 207 N = 201 % % Percentage of subjects 79 78 with adverse eventsBody as a whole Injection site adverse 35 <1 events** Weight increase* 912 Fatigue 3 6 Chills 5 0 Cardiovascular system Hot flush* 26 21Hypertension 6 4 Musculoskeletal system Back pain 6 8 Arthralgia 5 9Urogenital system Urinary tract infection 5 9 Digestive systemConstipation 5 5

There was no evidence of any clinically significant changes in liverfunction. Few elevations of the liver enzymes were seen, and thesechanges were generally mild and transient. Safety data from all clinicaltrials with degarelix in the treatment of prostate cancer, includingpatients receiving other dosing regimens, were pooled. The followingadverse reactions, not already listed, were reported to be drug-relatedby the investigator in ≥1% of patients: erectile dysfunction,gynaecomastia, hyperhidrosis, testicular atrophy, and diarrhea.

Decreased bone density has been reported in the medical literature inmen who have had orchiectomy or who have been treated with a GnRHagonist. It can be anticipated that long periods of medical castrationin men will have effects on bone density.

Advantages of the degarelix therapeutic dosing regimen for the treatmentof prostate cancer include a diminished likelihood of occurrence and/ordiminished severity of symptoms of adverse reactions, adverse events orside effects to other organs or tissues. An extensive panel of potentialadverse events related to drug therapies has been described.

An adverse reaction dictionary allows investigators to identify the sameadverse reaction with the same term and to identify different adversereactions with different terms. A standard dictionary may be used,however specialized pharmaceutical dictionaries have been develop todefine adverse reaction terms and their synonyms (see Gillum (1989) “TheMerck regulatory dictionary: A pragmatically developed drug effectsvocabulary” Drug Info. J. 23:217-220). The World Health Organization(WHO) Adverse Reaction Terminology is also available for delimiting themeanings of drug-induced side effects (see, e.g., Saltzman (1985)“Adverse reaction terminology standardization” Drug Info. J. 19:35-41).The Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART)system is also known in the art (see, e.g., NcNeil et al. (1982) N.Engl. J. Med. 306:1259-62; and Teal and Dimmig (1985) “Adverse drugexperience management” Drug Info. J. 19:17-25). These lists are oftendivided by body system and certain terms are annotated with alternativeclassifications.

COSTART provides a basis for vocabulary control of adverse reactionreports that emanate from a variety of sources. COSTART is organizedprimarily by anatomy. It has a hierarchical arrangement of terms, fromthe broadest (body-system categories) to the narrowest (specificpreferred terms or even special search categories). The COSTARTdictionary is used and maintained by the Center for Drugs and Biologicsat the Food and Drug Administration (FDA) for marketed medicinesurveillance and has been endorsed by many senior managers in thevarious reviewing sections. There are four indexes in COSTART: index A,comprising three lists including a body-system search categories, and aspecial search categories (e.g., neoplasia).

The WHO terminology system of adverse reactions is relatively short. Acode number is assigned to each of these terms. This provides theadvantage that the same code is retained when the term is translatedinto different languages. The WHO system uses a hierarchy of “preferredterms” to describe adverse reactions. Other commonly used terms arecalled “included terms,” which are listed with their preferred terms.

The FDA and many pharmaceutical companies have gone through an evolutionof systems in how they obtain, collect, process, and define adversereactions. The medicine dictionary that has been used by the FDA (“TheCenter for Drugs and Biologics Ingredient Dictionary”) is known in theart and its use in adverse event categorization has been addressed (see,e.g., Forbes et al. (1986) Drug Info. J. 20:135-45; and Turner et al.(1986) Drug Info. J. 20:147-50).

Certain advantages and disadvantages of COSTART, SNOMED and WHO AdverseReaction Terminology are reviewed by Stephens (“The Detection of NewAdverse Drug Reactions” pp. 18-124, Stockton Press, New York).

The MedDRA Medical dictionary for regulatory activities is aparticularly useful source for definitions of adverse events relating todrug trials. MedDRA utilizes pragmatic, medically valid terminology withan emphasis on ease of use for data entry, retrieval, analysis, anddisplay, as well as a suitable balance between sensitivity andspecificity within the regulatory environment. It was developed by theInternational Conference on Harmonisation (ICH) and is owned by theInternational Federation of Pharmaceutical Manufacturers andAssociations (IFPMA) acting as trustee for the ICH steering committee,and is readily available commercially (see, e.g., the MedDRA website atwww.meddramsso.com). The MedDRA Maintenance and Support ServicesOrganization (MSSO) holds a contract with the International Federationof Pharmaceutical Manufacturers Associations (IFPMA) to maintain andsupport the implementation of the terminology. MedDRA terminologyapplies to all phases of drug development, excluding animal toxicology,and has been utilized in the examples that follow.

As described in further detail below, a number of other adversereactions including cardiovascular anomalies (e.g., cardiac arrhythmias,coronary artery disorders and cardiac disorders), arthralgia, andurinary tract infection unexpectedly occur at a lower frequency thanprior art androgen depletion therapies such as the GnRH antagonistleuprolide.

Cardiovascular Disease

The invention includes methods for treating individuals with prostatecancer who are at risk for developing a cardiovascular disease, as wellas methods of treating otherwise normal prostate cancer patients with adecreased likelihood of developing a cardiovascular side effect. Thisaspect of the invention is particularly significant, in light of recentfindings suggesting the possibility of an increased risk of death fromnonprostate cancer causes, particularly relating to adverse effects oncardiovascular health, in patients being treated with prior art androgendeprivation therapies (see Yannucci et al. (2006) J. Urol. 176:520-5).

The indicia of risk for developing cardiovascular disease have beeninvestigated extensively and are known in the art (see, e.g., Wilson etal. (1998) Circulation 97:1837-47; Hackam (2003) JAMA 290:932-940).These cardiovascular risk factors include: high blood pressure(particularly greater than or equal to 130 over 85 mm Hg); high levelsof low-density lipoprotein cholesterol (particularly greater than orequal to 160 mg/dL); low levels of high-density lipoprotein cholesterol(particularly less than 35 mg/dL); high levels of serum glucose(particularly levels of fasting glucose levels greater than about 120mg/dL); high serum levels of C-reactive protein (CRP) (particularlylevels greater than 3 mg/dL); high serum levels of homocysteine(particularly levels greater than 30 μmol/L); high serum levels of serumfibrinogen (particularly levels greater than 7.0 g/L); and high serumlevels of lipoprotein(a) (Lp(a)) (particularly levels of greater than 30mg/dL). In addition, habitual smoking has been shown to be associatedwith an increased risk for cardiovascular disease.

Furthermore, the association of overall body weight, body mass index(BMI) and the presence of indicators of “metabolic syndrome” with riskfor cardiovascular disease have been reported (see e.g., Behn and Ur(2006) Curr. Opin. Cardiol. 21:353-60; and Romero-Corral et al. (2006)The Lancet 368:666-78).

The present disclosure further provides for methods for treatingprostate cancer in a subject with a history of at least onecardiovascular event, wherein administration of degarelix to the subjectdecreases the likelihood of developing or experiences an additionalcardiovascular event compared to treatment with a gonadotrophinreleasing hormone (GnRH) agonist.

This present disclosure is further illustrated by the examples thatfollow, which should not be construed as limiting.

EXAMPLES Example 1: Clinical Study of Degarelix for the Treatment ofProstate Cancer

In this example, an open-label, multi-center, randomized, parallel-groupstudy was conducted to investigate the efficacy and safety of degarelixone month dosing regimens. Patients in two degarelix treatment groupsreceived a degarelix starting dose of 240 mg at a concentration of 40mg/mL followed by either of two different once-a-month dosing regimens,160 mg (40 mg/mL) and 80 mg (20 mg/mL). These degarelix dosing regimenswere compared to LUPRON DEPOT™ at 7.5 mg in patients with prostatecancer requiring androgen ablation therapy.

The study also investigated whether degarelix is safe and effective withrespect to achieving and maintaining testosterone suppression tocastrate levels, evaluated as the proportion of patients withtestosterone suppression 0.5 ng/mL during 12 months of treatment, andcompared serum levels of testosterone and prostate-specific antigen(PSA) using a degarelix dosing regimen versus leuprolide 7.5 mg duringthe first 28 days of treatment. The study further compared the safetyand tolerability using a degarelix dosing regimen compared to treatmentwith leuprolide 7.5 mg, and, further, compared testosterone, luteinizinghormone (LH), follicle-stimulating hormone (FSH), and PSA response witha degarelix dosing regimen compared to leuprolide 7.5 mg. The studyfurther compared patient reported outcomes (quality of life factors andhot flushes) using a degarelix dosing regimen as compared to leuprolide7.5 mg during treatment. Finally, the study evaluated thepharmacokinetics of the degarelix dosing regimens investigated.

Study Design

A total of 620 patients were randomized 1:1:1 to one of three treatmentgroups. Of these, 610 patients were administered InvestigationalMedicinal Product (IMP). Ten randomized patients withdrew from the studybefore dosing.

Patients in two treatment groups received a degarelix starting dose of240 mg at a concentration of 40 mg/mL (240@40) on Day 0 administered astwo equivalent subcutaneous (s.c.) injections of 120 mg each.Thereafter, patients received 12 additional single s.c. degarelix dosesof either 80 mg at a concentration of 20 mg/mL (80@20: degarelix 240/80mg group) or 160 mg at a concentration of 40 mg/mL (160@40: degarelix240/160 mg group) administered s.c. every 28 days. In the thirdtreatment group, patients received active treatment with leuprolide 7.5mg on Day 0 and every 28 days administered as a single intramuscular(i.m.) injection. For patients receiving treatment with leuprolide 7.5mg, bicalutamide could be given as clinical flare protection at theInvestigator's discretion.

Patients were stratified according to geographic region (Central andEastern Europe, Western Europe and The Americas) and body weight (<90 kgand ≥90 kg).

Deqarelix 240/160 mg Group

This group received an initial dose of 240 mg at a concentration of 40mg/mL (240@40) on Day 0. This starting dose was administered as twoequivalent subcutaneous (s.c.) injections of 120 mg each. The group thenreceived 12 maintenance doses of 160 mg at a concentration of 40 mg/mL(160@40) as single s.c doses of degarelix every 28 days.

Degarelix 240/80 mg Group

This group also received an initial dose of 240 mg at a concentration of40 mg/mL (240@40) on Day 0. This starting dose was administered as twoequivalent s.c. injections of 120 mg each. The group then received 12maintenance doses of 80 mg at a concentration of 20 mg/mL (80@20) assingle s.c doses of degarelix every 28 days.

Leuprolide 7.5 mg Group

This group received the reference therapy leuprolide 7.5 mg. Thistreatment was administered as a single intramuscular (i.m.) injection,once every 28 days starting at Day 0.

TABLE 3 Treatment Methodology Treatment Group Starting Dose MaintenanceDoses Degarelix 240@40 (as 2 doses 160@40 (as 12 single 240/160 mg onDay 0) doses, one every 28 days) Degarelix 240@40 (as 2 doses 80@20 (as12 single doses, 240/80 mg on Day 0) one every 28 days) Leuprolide 7.5mg administered at Day 0 and every 28 days via 7.5 mg singleintramuscular injection. Bicalutamide was given at the Investigator'sdiscretion.

Patients were monitored on an ongoing basis and visited the clinic atmonthly intervals up to one year. Patients were observed clinically forat least 1 hour after each administration of study drug. Patients whocompleted the study and met appropriate criteria were offered theopportunity to receive long-term treatment and support in an extensionstudy.

A total of 807 patients were screened and 620 patients were randomized1:1:1 into three treatment groups, degarelix 240/160 mg, degarelix240/80 mg and leuprolide 7.5 mg. Of the 620 patients randomized, 610patients actually received study medication including 202, 207 and 201patients in the degarelix 240/160 mg, degarelix 240/80 mg and leuprolide7.5 mg treatment groups, respectively. A total of 504 patients completedthe study.

Diagnosis and Criteria for Study Inclusion

Males aged 18 years and over with histologically confirmed (Gleasongraded) adenocarcinoma of the prostate (all stages), in whom androgenablation treatment was indicated (except for neoadjuvant hormonaltherapy) were eligible to participate. Signed informed consent wasobtained before any study-related activity occurred. Patients were tohave a baseline testosterone level >1.5 ng/mL and a PSA level of ≥2ng/mL at the time of screening. Patients with rising PSA after havingundergone prostatectomy or radiotherapy with curative intent could beincluded in the study. Patients were required to have an ECOG score of≤2 and a life expectancy of at least 12 months. Previous or presenthormonal management of prostate cancer (surgical castration or otherhormonal manipulation, e.g. GnRH agonists, GnRH antagonists,antiandrogens, or estrogens) resulted in exclusion from the study.However, in patients having undergone prostatectomy or radiotherapy withcurative intention, neoadjuvant hormonal treatment was accepted for amaximum duration of 6 months provided that this treatment had beenterminated for at least 6 months prior to the screening visit.Concurrent treatment with a 5-α-reductase inhibitor also resulted inexclusion from the study. Patients who were candidates for a curativetherapy (i.e. radical prostatectomy or radiotherapy) were excluded.Patients with histories of severe hypersensitivity reactions orclinically significant disorders (other than prostate cancer) that mightaffect the conclusion of the study as judged by the Investigator werenot eligible to enter into the study. Patients with a marked baselineprolongation of QT/QTcF interval (>450 msec), had used concomitantmedications that may prolong QT/QTcF interval or who had a history ofadditional risk factors for Torsade de Pointes ventricular arrhythmiaswere excluded. Patients who had elevated serum ALT or total bilirubinlevels above upper level of normal range at the screening visit or whohad known or suspected hepatic, symptomatic biliary disease were alsoexcluded. Patients were also excluded if they had a knownhypersensitivity to any component of the investigational products. Inaddition, patients with any form of cancer within the last five years,with the exception of prostate cancer and surgically removed basal orsquamous cell carcinoma of the skin, were excluded from the study.Patients who had a mental incapacity or language barriers precludingadequate understanding or co-operation were also ineligible toparticipate in the study. No other investigational drug was to beadministered within 28 days preceding the screening visit.

Duration of Treatment

Patients in the degarelix treatment groups received a starting dose of240@40 on Day 0 and 12 maintenance doses of 160@40 (degarelix 240/160 mggroup) or 80@20 (degarelix 240/80 mg group) every 28 days.Administration of investigational medicinal products took place on Day0, Day 28 (±2 days) and every 28 day (±7 days) thereafter until the endof study visit; day 364 (±7 days). Patients who completed the study andmet appropriate criteria were offered the opportunity to receivelong-term treatment and support in an extension study.

Patients in the reference therapy group received treatment withleuprolide 7.5 mg on Day 0 and every 28 days thereafter for 12maintenance doses. Patients who completed the study received thirteendoses in total. Patients who completed the study and met appropriatecriteria were offered a switch to degarelix treatment in a continuingstudy. These patients were randomized to degarelix treatment 240/80 mgor 240/160 mg. On Day 0 of the study, patients previously treated withleuprolide 7.5 mg in study CS21 received a 240 mg (40 mg/mL) degarelixstarting dose followed by monthly maintenance doses of either 80 mg (20mg/mL) or 160 mg (40 mg/mL).

Patients in the comparator group were treated with leuprolide 7.5 mgpre-filled, dual-chamber syringe for intramuscular (i.m.) injection.Patients received leuprolide 7.5 mg on Day 0 and every 28 dayssubsequently, administered as a single i.m. injection. At theinvestigator's discretion, bicalutamide could be given as clinical flareprotection.

Criteria for Evaluation of Efficacy

The primary efficacy endpoint was the probability of testosterone levelsremaining ≤0.5 ng/mL from day 28 through day 364.

The secondary efficacy endpoints were: the proportion of patients withtestosterone surge during the first 2 weeks of treatment; the proportionof patients with testosterone level ≤0.5 ng/mL at day 3; the percentagechange in PSA from baseline to day 28; the probability of testosterone≤0.5 ng/mL from day 56 through day 364; the levels of serumtestosterone, LH, FSH and PSA over time through the study; the time toPSA failure, defined as two consecutive increases of 50%, and at least 5ng/mL as compared to nadir; degarelix concentration over the first monthand trough levels at day 308 and 336; the frequency and size oftestosterone increases at day 255 and/or 259 compared to thetestosterone level at day 252; the quality of life on days 0, 28, 84,168 and end of study visit; the frequency and intensity of hot flushesexperienced (scored daily from study start until end of study visit. Inaddition, two further secondary endpoints were added: the probability ofsufficient testosterone response from day 28 through day 364 (a patientwas considered to have insufficient testosterone response if he had onetestosterone value >1.0 ng/mL or two consecutive testosteronevalues >0.5 ng/mL at day 28 onwards); and the percentage change in PSAfrom baseline to Day 14.

Criteria for Evaluation of Safety

The safety variables for this study were assessed on the following: thefrequency and severity of adverse events (AEs); the presence ofclinically significant changes in laboratory parameters (clinicalchemistry, hematology and urinalysis); changes in electrocardiograms(ECGs) and vital signs; changes detected by physical examination; andbody weight.

An adverse event (AE) was defined as any untoward medical occurrence ina patient or clinical investigation subject administered aninvestigational medical product (IMP) and which did not necessarily havea causal relationship with the study treatment. An AE was therefore anyunfavorable or unintended sign (including an abnormal laboratoryfinding), symptom or disease temporally associated with the use of theproduct, whether or not related to the IMP.

This definition also included accidental injuries and reasons forchanges in medication (drug and/or dose), any medical, nursing orpharmacy consultation, or admission to hospital or surgical operations.It also included AEs commonly observed and AEs anticipated based on thepharmacological effect of the IMP. Any clinically significant injectionsite reaction of a severity requiring active management (i.e. change indose, discontinuation of study drug, more frequent follow-up ortreatment of the injection site) was also considered to be an AE and wasto be reported on the AE log. This definition was the minimumrequirement for reporting of an AE related to injection site reactions.There may have been situations where there was no active follow-up butthe reaction was still considered to be an AE.

An adverse drug reaction (ADR) was defined as an AE evaluated by theinvestigator as being probably or possibly related to treatment with theIMP.

An unexpected AE was defined as an AE not identified in nature,severity, or frequency in the section “undesirable effects” in thesponsor's current investigator's summary or in the leuprolide 7.5 mgpackage insert.

AEs could be volunteered spontaneously by the patient, or in response togeneral questioning about their well-being by the investigator, or as aresult of changes in systemic and local tolerability, laboratoryparameters or physical examinations. All AEs were recorded. The natureof each event, time and date of onset, duration, intensity, seriousnesscriteria, an assessment of its cause and relationship to the studymedication, the need for specific therapy and its outcome weredescribed. The action taken because of an AE was classified according tomedicinal product (no change, discontinued, other change [specified]).All medications used to treat the AE were recorded in the concomitantmedication log.

All patients experiencing AEs, whether considered associated with theuse of the study medication or not, were to be followed until the AEresolved, stabilized or the patient's participation in the study ended(i.e. until end of study visit was completed for that patient).

Any AE assessed by the investigator as serious, severe and/or possiblyor probably related to the investigational product was to be followeduntil it had resolved or until the medical condition of the patient wasstable and all relevant follow-up information had been reported toFerring Pharmaceuticals NS. In addition, any AE related to liverfunction test (LFT) was to be followed by the investigator. The outcomeof an AE was classified as recovered, recovered with sequelae, not yetrecovered or death.

All AEs, however minor, were documented whether or not the investigatorconsidered the event to be related to IMP. If an AE worsened inintensity and the patient did not recover between observations, a singleAE with the highest intensity was recorded. The AE reporting period wasfrom the time the patient signed the informed consent until the end ofstudy visit. AEs requiring therapy were treated with recognizedstandards of medical care to protect the health and well being of thepatient. Appropriate resuscitation equipment and medicines wereavailable to ensure the best possible treatment of an emergencysituation.

AEs were graded according to the National Cancer Institute (NCI) CommonTerminology Criteria for Adverse Events (CTCAE). In accordance with theCTCAE criteria, AEs were rated on a five-point scale corresponding tomild, moderate, severe, life-threatening or disabling and death. Forthose AEs not described in the CTCAE, a separate five-point rating scalewas used for rating of the intensity of AEs as follows below:

Grade 1 AEs: Mild—Minor; no specific medical intervention; asymptomaticlaboratory findings only, radiographic findings only; marginal clinicalrelevance.

Grade 2 AEs: Moderate—minimal intervention to local intervention, ornon-invasive intervention.

Grade 3: Severe—significant symptoms, requiring hospitalization orinvasive intervention; transfusion; elective interventional radiologicalprocedure; therapeutic endoscopy or operation.

Grade 4: Life-threatening or disabling—complicated by acute,life-threatening metabolic or cardiovascular complications such ascirculatory failure, haemorrhage, sepsis; life-threatening physiologicconsequences; need for intensive care or emergent invasive procedure;emergent interventional radiological procedure, therapeutic endoscopy oroperation.

Grade 5: Death.

Furthermore, a four-point scale was used for rating the causalrelationship of the AE to the investigational product as follows.

Probable—clear-cut temporal association with improvement on cessation oftest drug or reduction in dose; reappears upon re-challenge; follows aknown pattern of response to test drug.

Possible—follows a reasonable temporal sequence from administration; mayhave been produced by the patient's clinical state or by environmentalfactors or other therapies administered.

Unlikely—does not follow a reasonable temporal sequence fromadministration. May have been produced by the subject's clinical stateor by environmental factors or other therapies administered.

Unrelated—clearly and incontrovertibly due to extraneous causes, anddoes not meet criteria listed under unlikely, possible or probable.

Serious adverse events (SAEs) were defined as any untoward medicaloccurrence that at any dose resulted in death, was life-threatening,required in-patient hospitalization or prolongation of existinghospitalization, resulted in persistent or significantdisability/incapacity, was an important medical event or resulted in acongenital anomaly/birth defect.

The death of a patient enrolled in this study was not considered anevent per se, but rather an outcome. Any event resulting in a fataloutcome was fully documented and reported, including death, whichoccurred within the four weeks after treatment end, and regardless ofthe causality relationship to the IMP.

The term ‘life-threatening’ in the definition of SAEs referred to anevent in which the patient was at immediate risk of death at the time ofthe event. It did not refer to an event, which might have caused death,if it had been more severe.

Laboratory parameters (Table 4) were recorded at screening and duringthe study. Details of methodology and equipment used, and the normalranges for the various parameters are known in the art.

TABLE 4 Laboratory Parameters Haematology Clinical chemistry UrinalysisHaematocrit Albumin Haemoglobin Haemoglobin Alkaline Glucose Mean cellphosphatase Ketones haemoglobin Alanine White blood concentrationaminotransferase cells (MCHC) (ALT) Leucocytes Mean cell volumeAspartate pH (MCV) aminotransferase Protein Platelet count (AST) Casts,granular Reticulocytes Bicarbonate Casts, hyaline Red blood cell CalciumCasts, red blood count (RBC) Cholesterol cells White blood cellCreatinine Casts, waxy count (WBC) with Gamma- White blood celldifferential count glutamyltransferase casts (basophils, (Gamma-GT)Bacteria eosinophils, Potassium Cholesterol lymphocytes, Sodium Cystinecrystals monocytes, Total bilirubin Leucine crystals neutrophilsUrea/Blood urea Tyrosine nitrogen (BUN) crystals Uric Acid

In addition, blood samples taken pre-dose at day 0, day 168 and at theend of study visit were assessed for the presence of anti-degarelixantibodies.

Clinically significant laboratory abnormalities suggesting a disease ororgan toxicity and of a severity requiring active management (i.e.change of dose, discontinuation of drug, more frequent follow-up or adiagnostic investigation) were to be reported as AEs.

Blood pressures and pulse were measured at Screening, before dosing ateach dosing visit, and at the end of study visit. Diastolic and systolicblood pressure and pulse were measured after resting for five minutes ina sitting position. Patients were observed clinically for at least 1hour after each administration of investigational medical product (IMP)to observe for any immediate onset hypersensitivity reaction. During theobservation period, diastolic and systolic blood pressure and pulse weremeasured at 5, 10, 30 and 60 minutes after dosing.

A 12-lead electrocardiogram (ECG) was performed by site personnel atscreening, day 0, day 3, every 12 weeks (84 days) after day 0 and at theend of study visit. ECGs were performed before dosing, if a dosing visitwas scheduled. The ECGs were acquired digitally and the measurementswere performed as known in the art. The ECG measurements included heartbeat, PR, QRS intervals, QT and QTc, T and U wave.

Each patient also underwent a physical examination at screening, day 0,every 12 weeks thereafter and at the end of study visit. Any clinicallysignificant abnormal findings observed at screening were recorded. Anyclinically significant abnormal findings observed thereafter wererecorded as AEs.

Body weight was measured at screening and the end of study visit. Height(without shoes) was measured at screening. Body mass index (BMI) isdefined as the individual's body weight divided by the square of theirheight. The formulas universally used in medicine produce a unit ofmeasure of kg/m2. Body mass index may be accurately calculated using anyof the formulas below.

Statistical Methods

All statistical analyses were performed, and summary statisticscalculated, using statistical analysis software SAS™ version 9 orhigher. The populations for analysis were:

The intention-to-treat (ITT) analysis set included all randomizedpatients who received at least one dose of investigational medicinalproduct (IMP).

The per protocol (PP analysis set) comprised all the ITT analysis setwithout any major protocol violations

The safety population was identical to the ITT analysis set, andtherefore all safety analyses were performed on the ITT analysis set.

The primary efficacy endpoint was analyzed for both the ITT and PPanalysis sets, with the ITT analysis set considered primary. The primaryefficacy endpoint was analyzed using the Kaplan Meier method. For eachof the three treatment groups, testosterone response rates with 95%confidence interval (CI) were calculated by log-log transformation ofsurvivor function. Differences between the degarelix treatment groupsand leuprolide 7.5 mg were assessed using a 97.5% CI calculated bynormal approximation using pooled standard error.

To assess the efficacy of degarelix, two hypotheses were tested:

(1) The FDA criterion was to determine whether the lower bound of the95% confidence interval (CI) for the cumulative probability oftestosterone ≤0.5 ng/mL from Day 28 to Day 364 was no lower than 90%.

(2) The EMEA criterion was to determine whether degarelix wasnon-inferior to leuprolide 7.5 mg with respect to the cumulativeprobability of testosterone ≤0.5 ng/mL from Day 28 to Day 364. Thenon-inferiority limit for the difference between treatments (degarelixversus leuprolide 7.5 mg) was −10 percentage points.

All secondary efficacy endpoints were analyzed for both the ITT and PPanalysis sets, unless otherwise stated. The proportion of patients withtestosterone surge during the first 2 weeks of treatment was analyzedusing Fisher's exact test. Fisher's exact test was also used to analyzethe proportion of patients with testosterone level ≤0.5 ng/mL at day 3.The percentage change in PSA from baseline to day 28 endpoint wasanalyzed by a Wilcoxon test. For both Fisher's exact test and theWilcoxon test, separate data presentations were made by treatment group,geographic region, weight strata (<90 kg, ≥90 kg) and for the leuprolide7.5 mg subgroup.

The secondary endpoints; probability of testosterone ≤0.5 ng/mL from Day56 through Day 364, time to PSA failure and probability of sufficienttestosterone response from Day 28 through Day 364 were analyzed by theKaplan-Meier method.

Efficacy Results

The primary objective of this study was to demonstrate the effectivenessof degarelix in achieving and maintaining testosterone suppression tocastrate levels, evaluated as the proportion of patients withtestosterone suppression ≤0.5 ng/mL during 12 months of treatment.

The results show that degarelix delivered at the 240/80 mg dosingregimen produced a rapid and effective suppression in testosteronelevels, which remained low throughout the 364 day period of treatment(FIG. 2 ).

Kaplan-Meier estimates of the probabilities of testosterone ≤0.5 ng/mLfrom day 28 to day 364 were 98.3%, 97.2% and 96.4% for the degarelix240/160 mg, degarelix 240/80 mg and leuprolide 7.5 mg groups,respectively. For all three treatment groups the lower bound of the 95%CI was above the pre-specified 90% threshold. Treatment with degarelixwas demonstrated to be non-inferior to leuprolide 7.5 mg therapy withrespect to the probability of testosterone ≤0.5 ng/mL from day 28 to day364. For both degarelix treatment groups, the entire 97.5% CI for thedifference in probability compared with the leuprolide 7.5 mg group wasgreater than the non-inferiority limit of −10 percentage points. Thusthe study fulfilled the FDA and EMEA criteria for efficacy.

The robustness of the results for the primary efficacy endpoint wassupported by an observed cases analysis, which produced similarestimates of the overall proportion of patients with testosterone ≤0.5ng/mL from day 28 to day 364 for the degarelix 240/160 mg, degarelix240/80 mg and leuprolide 7.5 mg groups of 98.2%, 97.0% and 96.0%,respectively. The findings of the primary analysis were furthersupported by a secondary efficacy analysis of the probability oftestosterone ≤0.5 ng/mL from day 56 to day 364.

As expected, a significantly higher proportion of patients in theleuprolide 7.5 mg group (80.1%) had a testosterone surge (increase ≥15%from baseline) during the first two weeks of treatment compared with thepooled degarelix groups (0.2%: one patient) (p<0.0001, Fisher's exacttest). The patient treated with degarelix can be considered to be anartifact as this patient had low testosterone at baseline (0.0065 ng/mL)thus a surge from such a low baseline value was not remarkable.Conversely, 96% of patients receiving degarelix exhibited testosteronesuppression on day 3 compared with no patients in the leuprolide 7.5 mggroup (p<0.0001, Fisher's exact test). As shown in FIG. 3 , thedegarelix 240/80 mg dosing regimen rapidly and efficiently suppressedtestosterone levels, while Lupron 7.5 mg acted much more gradually andonly after an initial testosterone surge.

The profiles for serum levels of LH over time were similar to thoseobserved for testosterone. Following administration of degarelix, medianLH levels for the ITT analysis set decreased rapidly and were <0.7 IU/Lon day 1, a decrease of approximately 88% from baseline. For bothdegarelix treatment groups median LH levels remained suppressed untilthe end of the study on day 364. In contrast, a surge in median LHlevels was observed for patients in the leuprolide 7.5 mg group, whichpeaked at 31.0 IU/L on day 1 (>400% increase from baseline) beforedecreasing exponentially to 0.035 IU/L by day 56 and remaining at thislevel until day 364 (see FIG. 4 ).

A rapid decrease in FSH levels was also observed in patients treatedwith degarelix. Administration of degarelix resulted in a reduction inmedian FSH levels to ≤1.5 IU/L by day 7, a >80% decrease from baseline.For both degarelix treatment groups median FSH levels remainedsuppressed until the end of the study on day 364. For patients in theleuprolide 7.5 mg group there was an initial surge in FSH levels similarto that observed for LH levels which peaked at 22.5 IU/L on day 1 (146%increase from baseline) before decreasing exponentially to 2.0 IU/L byday 14. Median FSH subsequently increased around day 56 to a plateau ofapproximately 4.40 IU/L and stayed there until day 364 (see FIG. 5 ).

As shown in FIG. 6 , the degarelix 240/80 mg dosing regimen alsoproduced a more rapid and efficient reduction in PSA levels than didtreatment with Lupron 7.5 mg. A rapid reduction in PSA levels wasobserved for patients treated with degarelix. In contrast, PSA levels inthe leuprolide 7.5 mg group reached a plateau during the first week oftreatment before decreasing exponentially to suppressed levels. Therewas a significantly greater reduction in median PSA levels from baselinethat was observed on day 14 and day 28 for degarelix patients comparedwith leuprolide 7.5 mg patients (p<0.0001, Wilcoxon test). Theprobability of a PSA observation from the pooled degarelix groups beingless than one from the leuprolide 7.5 mg group was slightly higher onday 14 (0.82) than on day 28 (0.70). The probability of completing thestudy without experiencing PSA failure was highest in the degarelix240/80 group (91.2%) and slightly lower (˜85.8%) for both the degarelix240/160 mg and leuprolide 7.5 mg groups, although this difference wasnot statistically significant.

Anti-androgen therapy, as per protocol, was given to 22 patients in theleuprolide 7.5 mg group at the start of treatment for flare protection.PSA data for these patients showed a greater median percentage changefrom baseline at day 14 (61.7% reduction) and day 28 (89.1%) compared tothose patients in the leuprolide 7.5 mg group who did not receiveanti-androgen therapy where the percentage reduction was 15.3% and 61.7%at days 14 and 28, respectively. It should be noted that the medianpercentage change in PSA levels in the leuprolide plus antiandrogenpatients was similar to those patients treated with degarelix, therebyconfirming that degarelix is more effective than conventional GnRHagonist therapy at suppressing PSA at the start of treatment. Degarelixdoes not require additional concomitant medication as prophylaxis forflare, yet a starting dose of 240 mg has a similar effect on PSA levelsas the combination of GnRH agonist plus anti-androgen.

The pharmacodynamic profile for degarelix was characteristic of a GnRHantagonist with serum levels of testosterone, LH and FSH suppressedrapidly. In contrast, for patients in the leuprolide 7.5 mg group, serumlevels of testosterone, LH and FSH increased rapidly within the firstweek of treatment before falling to suppress levels.

Safety Results

Safety and tolerability were evaluated by observed and reportedtreatment-emergent AEs, including injection site reactions,haematological, clinical chemistry and urinalysis laboratory parameters,vital signs/clinical observations, and body weight measurements andphysical examination, ECGs and concomitant medication.

Safety parameters were evaluated for all patients included in the ITTanalysis set, comprising all 610 randomized patients who received atleast one dose of study medication. All safety tables include fourcolumns: the three treatment groups described separately, and the pooleddegarelix group.

Brief Summary of Adverse Events

Adverse events were regarded as ‘treatment-emergent’ if they occurred inthe time interval from initial dosing to end-of-study. Adverse eventswere considered ‘pre-treatment’ if they occurred between screening andthe initial injections of IMP. As described above, all AEs wereclassified according to MedDRA (version 10.0) system organ class (SOC),sorted alphabetically, and by preferred term (PT), in decreasingfrequency of occurrence. Treatment-emergent AEs were expressed in termsof intensity (using NCI CTCAE) and relationship to study drug. Anoverall summary of treatment-emergent AEs is presented in Table 5.

TABLE 5 Overall Summary of Treatment-Emergent Adverse Events TreatmentGroup Degarelix Leuprolide Adverse events 240/160 mg 240/80 mg Total 7.5mg category N (%) E N (%) E N (%) E N (%) E ITT analysis set 202(100%)   207 (100%)   409 (100%)   201 (100%)   All AEs 167 (83%) 941163 (79%) 937  330 (81%) 1878 156 (78%) 777 Deaths (Grade 5) 5 ( 2%) 6 5( 2%) 5 10 ( 2%) 11  9 ( 4%) 10 Serious AEs 24 (12%) 41 21 (10%) 26 45(11%) 67 28 (14%) 54 AEs leading to 19 ( 9%) 19 15 ( 7%) 15 34 ( 8%) 3412 ( 6%) 12 discontinuation ADRs 120 (59%) 463 118 (57%) 459 238 (58%)922 84 (42%) 146 N = number of patients with adverse events % =percentage of patients with adverse events E = number of adverse eventsADR = AE assessed by investigator as possibly/probably related toinvestigational product Common Toxicity Criteria for Adverse Events usedfor intensity grading

The overall percentages of patients experiencing treatment-emergent AEswere comparable across all three treatment groups. 167 (83%) patients inthe degarelix 240/160 mg group reported treatment-emergent AEs, comparedwith 163 (79%) patients in the degarelix 240/80 mg group, and 156 (78%)patients in the leuprolide 7.5 mg group. In total, there were reports ofADRs in 238 (58%) pooled degarelix patients, with 120 (59%) patients inthe degarelix 240/160 mg group, 118 (57%) patients in the degarelix240/80 mg group. For the leuprolide 7.5 mg group, 42% patients reportedADRs. This difference was expected and could be accounted for entirelyby injection-related AEs, which exhibited higher rates in the degarelixpooled arms. Excluding injection-site ADRs, the incidences of theremaining ADRs were similar in the three treatment groups:

88 (44%) patients reported ADRs, excluding injections site reactions, inthe degarelix 240/160 mg group

90 (43%) patients reported ADRs, excluding injections site reactions, inthe degarelix 240/80 mg group

84 (42%) patients reported ADRs, excluding injections site reactions, inthe leuprolide 7.5 mg group.

Such results suggest that both the degarelix maintenance doses (80@20mg/mL or 160@40 mg/mL) resulted in a similar incidence of ADRs.

A total of 45 (11%) pooled degarelix patients reported 67 serious AEs,including ten deaths. Overall, 24 (12%) patients in the degarelix240/160 mg group reported serious AEs, compared with 21 (10%) patientsin the degarelix 240/80 mg group, and 28 (14%) patients, including 9deaths, in the leuprolide 7.5 mg group. All deaths were assessed to beunrelated or unlikely to be related to study treatment. Such resultsshould also be interpreted in the knowledge that this is an elderlypatient population (mean age 72 years) with both prostate cancer andother underlying health issues.

Thirty-four (8%) pooled degarelix patients were reported as beingwithdrawn due to AEs (including both fatal and non-fatal AEs); 19 (9%)patients in the degarelix 240/160 mg group and 15 (7%) patients in thedegarelix 240/80 mg group, and there were 12 (6%) patients withdrawn inthe leuprolide 7.5 mg group. Of the pooled degarelix patients, therewere reports for 17 patients of SAEs that led to withdrawal.

Detailed Analysis of Adverse Events

While the overall occurrence of adverse events was similar in the twodegarelix treatment groups and the leuprolide control group, a largemajority of such events for the degarelix treatment groups were mereinjection site reactions related to the subcutaneous/depot deliverysystem employed for degarelix. In comparison, leuprolide intramuscularinjection was not associated with such a high rate of injection sitereactions even though the overall rate of adverse occurrence wassimilar. Accordingly, a detailed analysis of the precise type of adverseevents occurring in each study group was undertaken to characterize thetypes of adverse events, other than injection site reactions, that mustbe occurring in the leuprolide treatment group to account for theoverall similar adverse event occurrence rates.

Table 6 shows a summary of the number of patients reportingtreatment-emergent AEs, presented by SOC. All treatment-emergent AEs arepresented by system organ class and Med-DRA preferred term.

TABLE 6 Treatment-Emergent Adverse Events by System Organ ClassTreatment Group Degarelix Leuprolide 240/160 mg 240/80 mg Total 7.5 mgMedDRA System Organ Class N (%) N (%) N (%) N (%) ITT analysis set 202(100%) 207 (100%) 409 (100%) 201 (100%) Treatment-emergent adverseevents 167 (83%) 163 (79%) 330 (81%) 156 (78%) BLOOD & LYMPHATIC SYSTEMDISORDERS 11 ( 5%) 5 ( 2%) 16 ( 4%) 12 ( 6%) CARDIAC DISORDERS 19 ( 9%)17 ( 8%) 36 ( 9%) 27 (13%) CONGENITAL, FAMILIAL & GENETIC DISORDERS 1(<1%) EAR & LABYRINTH DISORDERS 3 ( 1%) 6 ( 3%) 9 ( 2%) 3 ( 1%)ENDOCRINE DISORDERS 2 (<1%) 2 (<1%) 3 ( 1%) EYE DISORDERS 4 ( 2%) 6 (3%) 10 ( 2%) 5 ( 2%) GASTROINTESTINAL DISORDERS 33 (16%) 38 (18%) 71(17%) 39 (19%) GENERAL DISORDERS & ADMINISTRATION SITE 102 (50%) 92(44%) 194 (47%) 36 (18%) CONDITIONS HEPATOBILIARY DISORDERS 2 (<1%) 2(<1%) 4 (<1%) 3 ( 1%) IMMUNE SYSTEM DISORDERS 1 (<1%) 1 (<1%) 2 (<1%)INFECTIONS & INFESTATIONS 38 (19%) 45 (22%) 83 (20%) 49 (24%) INJURY,POISONING & PROCEDURAL 11 ( 5%) 10 ( 5%) 21 ( 5%) 17 ( 8%) COMPLICATIONSINVESTIGATIONS 58 (29%) 54 (26%) 112 (27%) 62 (31%) METABOLISM &NUTRITION DISORDERS 26 (13%) 14 ( 7%) 40 (10%) 15 ( 7%) MUSCULOSKELETAL& CONNECTIVE TISSUE 37 (18%) 31 (15%) 68 (17%) 53 (26%) DISORDERSNEOPLASMS BENIGN, MALIGNANT & UNSPECIFIED 12 ( 6%) 10 ( 5%) 22 ( 5%) 16( 8%) (INCL CYSTS AND POLYPS) NERVOUS SYSTEM DISORDERS 27 (13%) 24 (12%)51 (12%) 23 (11%) PSYCHIATRIC DISORDERS 16 ( 8%) 16 ( 8%) 32 ( 8%) 21(10%) RENAL & URINARY DISORDERS 26 (13%) 28 (14%) 54 (13%) 39 (19%)REPRODUCTIVE SYSTEM & BREAST DISORDERS 13 ( 6%) 9 ( 4%) 22 ( 5%) 21(10%) RESPIRATORY, THORACIC & MEDIASTINAL 17 ( 8%) 25 (12%) 42 (10%) 18( 9%) DISORDERS SKIN & SUBCUTANEOUS TISSUE DISORDERS 21 (10%) 18 ( 9%)39 (10%) 10 ( 5%) SURGICAL & MEDICAL PROCEDURES 2 (<1%) 2 (<1%) VASCULARDISORDERS 65 (32%) 71 (34%) 136 (33%) 60 (30%) N = number of patientswith adverse events % = percentage of patients with adverse events

Treatment-emergent AEs were reported for a comparable percentage ofpatients across all three treatment groups: 83%, 79% and 78% of patientsin the degarelix 240/160 mg, degarelix 240/80 mg and leuprolide 7.5 mggroups, respectively. As shown in Table B above, there were no markeddifferences between the SOCs affected for the two degarelix treatmentgroups. The predominant system-organ class affected for degarelixpatients in both treatment groups was ‘General Disorders andAdministration Site Conditions’, reported for 47% pooled degarelixpatients, and 18% leuprolide 7.5 mg patients. The majority of these AEswere injection site pain, which occurred in 29% of pooled degarelixpatients. In addition, ‘vascular disorders’ were reported for 33%degarelix patients, and 30% leuprolide 7.5 mg patients, primarily hotflushes. Other SOCs affected in ≥15% patients were: ‘investigations’ in27% degarelix patients and 31% leuprolide 7.5 mg patients, ‘infectionsand infestations’ in 20% and 24% patients, respectively,‘musculoskeletal and connective tissue disorders’ in 17% and 26%patients, respectively, and ‘gastrointestinal disorders’ in 17% and 19%patients, respectively. The most frequent musculoskeletal and connectivetissue disorders were back pain, reported by 6% of degarelix patientsand 8% of leuprolide 7.5 mg patients, and arthralgia reported for 4% ofdegarelix patients and 9% of leuprolide 7.5 mg patients.

In examining the SOCs of AEs associated with degarelix treatment ascompared to leuprolide, several areas of increased risk for leuprolideas compared to degarelix emerged. For example, ‘musculoskeletal andconnective tissue disorders’ occurred in 26% of leuprolide patients, ascompared to only 17% of degarelix patients overall (and even lower, 15%in the degarelix 240/80 mg treatment group). Furthermore, ‘renal andurinary disorders’ occurred in 19% of leuprolide patients, but only 13%of degarelix patients, while ‘reproductive system and breast disorders’occurred in 10% of leuprolide patients, but only 5% of degarelixpatients. Furthermore, ‘cardiac disorders’ occurred at a slightlyincreased overall frequency for leuprolide treatment (13%) than fordegarelix (9% overall between the two treatment groups). This may be ofparticular interest, since, as addressed above, there is some concern inthe art that certain androgen deprivation therapies adversely affectcardiovascular health (see Yannucci et al. (2006) J. Urology176:520-525; and Etzioni et al. (1999) J. Natl. Canc. Inst. 91:1033).Accordingly, androgen deprivation therapies that minimize the risk ofcardiovascular side effects are particularly desirable.

The increased risk for cardiac disorders, musculoskeletal and connectivetissue disorders, renal and urinary disorders, and reproductive systemdisorders for leuprolide as compared to degarelix likely account for theoverall similarity in adverse events between leuprolide and degarelix,despite the fact that most of the adverse events seen with degarelixwere mere injection site reactions related to the mode of subcutaneousdelivery and not to adverse systemic effects on other organ systems.

As shown in Table 7, the most frequently reported treatment-emergent AEsfor patients treated with degarelix were injections site reactions(particularly injection site pain and erythema). The most frequentlyreported AE for both degarelix and leuprolide patients during the studywere flushing events: overall, 52 (26%) patients in the degarelix240/160 mg group reported hot flushes, compared to 53 (26%) patients inthe degarelix 240/80 mg group, and 43 (21%) patients in the leuprolide7.5 mg group.

TABLE 7 Adverse Events by System Organ Class and Preferred TermOccurring in ≥5% of any Treatment Group Treatment Group DegarelixLeuprolide MedDRA System Organ Class/ 240/160 mg 240/80 mg Total 7.5 mgPreferred Term N (%) N (%) N (%) N (%) ITT analysis set 202 (100%) 207(100%) 409 (100%) 201 (100%) Treatment-emergent adverse events 167 (83%)163 (79%) 330 (81%) 156 (78%) GASTROINTESTINAL DISORDERS 33 (16%) 38(18%) 71 (17%) 39 (19%) Nausea 11 ( 5%) 9 ( 4%) 20 ( 5%) 8 ( 4%)Constipation 6 ( 3%) 11 ( 5%) 17 ( 4%) 10 ( 5%) GENERAL DISORDERS AND102 (50%) 92 (44%) 194 (47%) 36 (18%) ADMINISTRATION SITE CONDITIONSInjection site pain 61 (30%) 58 (28%) 119 (29%) 1 (<1%) Injection siteerythema 48 (24%) 36 (17%) 84 (21%) Injection site swelling 14 ( 7%) 13( 6%) 27 ( 7%) Fatigue 13 ( 6%) 7 ( 3%) 20 ( 5%) 13 ( 6%) Injection siteinduration 11 ( 5%) 8 ( 4%) 19 ( 5%) Injection site nodule 13 ( 6%) 6 (3%) 19 ( 5%) Chills 7 ( 3%) 11 ( 5%) 18 ( 4%) INFECTIONS ANDINFESTATIONS 38 (19%) 45 (22%) 83 (20%) 49 (24%) Urinary tract infection3 ( 1%) 10 ( 5%) 13 ( 3%) 18 ( 9%) INVESTIGATIONS 58 (29%) 54 (26%) 112(27%) 62 (31%) Weight increased 22 (11%) 18 ( 9%) 40 (10%) 24 (12%)Alanine aminotransferase increased 17 ( 8%) 20 (10%) 37 ( 9%) 11 ( 5%)Aspartate aminotransferase increased 10 ( 5%) 11 ( 5%) 21 ( 5%) 6 ( 3%)METABOLISM AND NUTRITION DISORDERS 26 (13%) 14 ( 7%) 40 (10%) 15 ( 7%)Hypercholesterolaemia 12 ( 6%) 7 ( 3%) 19 ( 5%) 5 ( 2%) MUSCULOSKELETALAND CONNECTIVE 37 (18%) 31 (15%) 68 (17%) 53 (26%) TISSUE DISORDERS Backpain 12 ( 6%) 12 ( 6%) 24 ( 6%) 17 ( 8%) Arthralgia 6 ( 3%) 11 ( 5%) 17( 4%) 18 ( 9%) VASCULAR DISORDERS 65 (32%) 71 (34%) 136 (33%) 60 (30%)Hot flush 52 (26%) 53 (26%) 105 (26%) 43 (21%) Hypertension 14 ( 7%) 12( 6%) 26 ( 6%) 8 ( 4%) N = number of patients with adverse events % =percentage of patients with adverse events

Long-term treatment with degarelix and leuprolide 7.5 mg was anticipatedto result in adverse reactions associated with testosterone suppressionsuch as hot flushes, loss of libido, impotence and infertility, andincreased sweating. It was therefore to be expected that flushing eventswould be relatively common and largely considered possibly or probablyrelated to treatment. However, very few AEs related to sexualdysfunction or sweating were reported. In total, there were reports for22 (5%) pooled degarelix patients and 21 (10%) leuprolide patients withreproductive system/breast disorders and approximately 1% patientstreated with degarelix with sweating disorders (skin and subcutaneoustissues SOC): six (1%) of patients reported erectile dysfunction, six(1%) of patients reported night sweats, four (<1%) of patientsexperienced testicular pain, three (<1%) of patients reported pelvicpain, three (<1%) of patients reported hyperhidrosis, two (2%) ofpatients each experienced gynaecomastia, prostatitis or testicularatrophy, and all other reproductive system/breast disorders werereported by one (<1%) of patients, and no other sweating disorders werereported.

An analysis of these SOC/preferred term data further support the findingdiscussed above for diminished musculoskeletal disorders, and renal andurinary disorders for degarelix as compared to leuprolide treatments.For example, 9% of leuprolide patients experienced urinary tractinfections during the course of treatment as compared to only 3% of alldegarelix-treated patients. Similarly, 9% of leuprolide patientsexperienced arthralgia (joint pain) during the course of treatment whileonly 4% of all degarelix-treated patients experienced arthralgia.

To summarize, the incidence of treatment-emergent AEs was similar forpatients treated with degarelix and leuprolide 7.5 mg.Treatment-emergent AEs were reported by 330 (81%) patients in the pooleddegarelix treatment groups and by 156 (78%) patients in the leuprolide7.5 mg group. The majority of AEs were of mild or moderate intensity.

There were 58% of patients treated with degarelix with reported AEsconsidered to be possibly/probably related to IMP by the Investigator(ADR) and those treated with leuprolide 7.5 mg had 42% ADRs, however themajority of treatment-emergent ADRs were general disorders andadministration site conditions including injection-site reactions whichoccurred in 173 (42%) patients in the pooled degarelix group. Forpatients treated with degarelix, the overall incidence oftreatment-emergent injection site reactions was 4.4 per 100 injections.Most injection site reactions occurred after the first dose of degarelixwhere two injections were administered and injection site reactions weredecreased over time. Among MedDRA preferred terms, the highestincidences were injection site pain (2.9 per 100 injections) andinjection site erythema (1.9 per 100 injections) for the pooleddegarelix group. All other preferred terms had an incidence rate of 0.5per 100 injections or less. None of the injection-related ADRs wereconsidered to be serious, and there were no immediate onsethypersensitivity reactions. Five (1.2%) patients reporteddegarelix-related injection site reactions, which led to withdrawal.Other commonly reported ADRs were hot flushes which were an expectedadverse reaction associated with testosterone suppression. In total, hotflushes were reported by 104 (25%) patients treated with degarelix and42 (21%) treated with leuprolide 7.5 mg. One patient treated withdegarelix reported a hot flush ADR, which led to withdrawal. Notably,although AEs related to sexual dysfunction would be anticipated toresult from testosterone suppression, very few were actually reported.

There were 121 serious adverse events SAEs reported by 73 (12%)patients, with relatively equal incidence across the treatment groups.The most common SAEs were cardiac disorders, which occurred in ten (2%)patients in the pooled degarelix group and ten (5%) patients in theleuprolide 7.5 mg group; and renal and urinary disorders, which occurredin 10 (2%) patients in the pooled degarelix group and six (3%) patientsin the leuprolide 7.5 mg group.

Weight increase is a known effect of androgen deprivation and markedlyabnormal increases in weight of ≥7% from baseline were observed in 10%patients treated with degarelix and 13% patients treated with leuprolide7.5 mg. The incidence of other markedly abnormal changes in vital signswas consistent with a group of elderly patients many of whom had amedical history of cardiac disease or hypertension.

Therefore, while degarelix treatment resulted in a significant number ofsubjects experiencing minor injection site reactions, these adverseeffects were remarkably less serious than many of those associated withthe GnRH agonist leuprolide. Notably, these minor injection sitereactions were also much less serious than the potentiallylife-threatening effects associated with another GnRH antagonist,Abarelix (Plenaxis in the U.S.) (seewww.fda.gov/cder/drug/infopage/plenaxis). Indeed Abarelix/Plenaxis hasbeen associated with serious allergic reactions (e.g., swelling of thetongue/throat, asthma, wheezing and serious breathing problems), andtherefore is only available through a special “user safety program” toensure that it is safely used by doctors with the right skills toadminister and monitor the drug.

Further Statistical Analyses of Subgroup Populations

Further statistical analysis of the CS21 clinical study results wasundertaken in order to determine whether any of the advantages insuperior efficacy and/or diminished side effects of degarelix overleuprolide treatment were particularly pronounced in certain patientsubgroups. Particular attention was paid to whether particular patientsubgroups were responsible for any of the diminished cardiac, arthralgicand/or urinary tract infection side effects seen with degarelixtreatment as compared to leuprolide treatment.

Using the results from the summary of clinical efficacy (SCE) andsummary of clinical safety (SCS) findings, different patient subgroupswere analyzed. Subgroup distinguishers included race (white, black, andother), age (<65 years, ≥65 years to <70 years, and >75 years), weight(<70 kg, ≥70−<90 kg, and ≥90 kg), body mass index (BMI) (≤20, >20 to 30,and >30 kg/m²)), region (North-America, Western Europe, Central andEastern Europe and Other), and stage of prostate cancer (e.g.,localized, locally advanced, and metastatic).

The SCS summarizes both crude incidences (n/N) as well as incidencerates of adverse events (number of patients with at least one adverseevent investigated per 1,000 person years) including exact 95% CI basedon the Poisson model and presented per MedDRA Preferred term (andgrouped by SOC) for all study-groups, including the CS21 trial (thetrial comprising the controlled phase 3 study group) and for allsub-groups. Briefly, the Poisson model provides exact 1-α lower (LL) andupper (UL) confidence limits are LL=χ_(2x; α/2) ²/(2T) andUL=χ_(2(x+1); 1-α/2) ²/(2T), respectively, where T is the number of1,000 person years and x=number of subjects at least once havingreported the adverse event under investigation (see Gerlinger et al.(2003) Eur. J. Contracept. Reprod. Health Care 8:87-92).

For the phase 3 controlled study (CS21), crude incidences in thedegarelix arms were compared to those in the leuprolide 7.5 mg arm usingtwo-sided Fisher exact test and corresponding P-value as a flaggingdevice. These P values were presented as *(0.01<P≤0.05), **(0.001<P≤0.01), and *** (P≤0.001). Similarly, incidence rates werecompared using P values associated with the Poison model-based UMPUtest. Briefly, assuming x_(i)˜Poisson(λ_(i)T_(i)), where xi=the numberof subjects with the event, T_(i)=total number of 1,000 person years inarm i and λ_(i)=incidence rate in arm i (i=1,2), then the P value=2 min(P(S≥1), P(S≤x₁), 0.5), where S˜Binomial (x₁+x₂, T₁/(T₁+T₂)) (see, e.g.Lehmann (1986) Testing Statistical Hypotheses, 2^(nd) edition,Springer-Verlag, New York).

Based on these results all adverse events (on SOC or PT level) thatdemonstrated a statistically significantly (P<=0.05) or borderlinesignificantly (0.05<P<0.2) lower incidence or incidence rate in thedegarelix arm as compared to leuprolide 7.5 mg were identified.

In the SCS, cardiovascular events were more specifically investigated onmore aggregated MedDRA levels, i.e. the incidence, and incidence ratesof subject with AEs in the following High Level Group Terms weretabulated by study group and treatment:

HLGT=Central nervous system vascular disorders

HLGT=Cardiac arrhythmias

HLGT=Coronary artery disorders

HLGT=Heart failures

To further substantiate apparent, but potentially isolated evidence on adetailed Preferred Term level that degarelix shows lower incidence ratesthan leuprolide with regard to specific cardiac disorders, the incidencerates with regard to the above-mentioned HLGTs, as well as theSOC═Cardiac Disorders these HLGTs belong to, were tested with regard tosubgroups based on possible risk-factor (cholesterol, BMI, body weight,systolic/diastolic blood pressure, medical history of cardiac disorder,age, pulse). These subgroup analyses were not pre-planned as part of theSCS. By testing statistical significance of risk-factor by treatment(degarelix/leuprolide 7.5 mg) interaction in a time to event analyses(Cox Proportional hazard model) these covariates were screened forpotential subgroup effects. Body mass index and to a lesser extentcholesterol were identified accordingly. Next, BMI subgroups (<25, 25 to<30, and 30 kg/m2) and low/normal cholesterol subgroups (4 mmol/L and >4mmol/L, respectively) were used to test and quantify differences inincidence rates between degarelix and leuprolide, along using thePoisson model mentioned above. Statistically significant lower incidencerate as compared to leuprolide were noted in patients with BMI <25 kg/m2with regard to SOC═Cardiac Disorders (P=0.0045), HLGT=Coronary arterydisorders (P=0.005), and HLGT=Cardiac Arrhythmias (borderline, P=0.056),with Relative risks of respectively 0.242 (95% CI: 0.08-0.67), 0.0 (95%CI: 0.0-0.47), and 0.312 (95% CI: 0.09-1.03]). Statisticallysignificantly lower incidence rate as compared to leuprolide were notedin patients with Cholesterol greater than or equal to 4 mmol/L withregard to HLGT=Cardiac Arrhythmias (P=0.035), with relative risks ofrespectively 0.41 (95% CI: 0.18-0.94).

See Tables 8-10 for efficacy findings in subgroups from the SCE, Tables11-19 for subgroup findings from the SCS, and Tables 20-23 for theexplorative substantiating subgroup findings on cardiovascular risk. Insummary, notable findings include:

Time to testosterone escape during Days 28, 56, . . . , 364 in the age<65 subgroup is significantly superior to LUPRON DEPOT® 7.5 mg for bothdegarelix dosing regimens (see Table 8 below).

TABLE 8 One year efficacy results for the testosterone endpoints forControlled Study CS21-in the age <65 subgroup Probability Probability oftestosterone of testosterone Probability of ≤0.5 ng/mL ≤0.5 ng/mLsufficient from Day 28 from Day 56 testosterone through Day 364 throughDay 364 response* Dosing regimen (%) 95% Cl N (%) 95% Cl N (%) 95% Cl NDegarelix 97.4% 82.8;99.6% 43 97.4% 82.8;99.6% 43 97.4% 82.8;99.6% 43240@40/80@20 Degarelix 96.7% 78.6;99.5% 37 96.7% 78.6;99.5% 37 96.7%78.6;99.5% 37 240/160@40 LUPRON 89.5% 74.3;95.9% 38 89.5% 74.3;95.9% 3892.1% 77.5;97.4% 38 DEPOT ® 7.5 mg Log-rank test: Degarelix p = 0.1318 p= 0.1318 p = 0.2588 240@40/80@20 vs. LUPRON DEPOT ® 7.5 mg Degarelix p =0.1851 p = 0.1851 p = 0.3373 240/160@40 vs. LUPRON DEPOT ® 7.5 mg Note:P values as flagging device used only in the Phase 3 study (head to headcomparison to LUPRON DEPOT 7.5 mg), ^(*) = 0.01 < P ≤ 0.05, ^(**) =0.001 < P ≤ 0.01, ^(***) = P ≤ 0.001 (Fisher exact, two-sided).

Time to PSA failure is significantly (P=0.03) superior in the degarelix240/80 mg group as compared to LUPRON DEPOT® 7.5 mg in the age >75 yeargroup, and also (P=0.06) significantly better in the <65 age group (seeTable 9 below).

TABLE 9 One year efficacy results for the PSA endpoints for ControlledStudy CS21—by age subgroups Probability of no PSA failure* Dosingregimen (%) 95% CI N Age (years) = <65 Degarelix 240@40/80@20 85.2%70.0; 93.1% 43 Degarelix 240/160@40 71.6% 53.6; 83.6% 37 LUPRON DEPOT ®7.5 mg 68.2% 50.9; 80.6% 38 Log-rank test: Degarelix 240@40/80@20 vs. p= 0.0679 LUPRON DEPOT ® 7.5 mg Degarelix 240/160@40 vs. p = 0.7273LUPRON DEPOT ® 7.5 mg Age (years) = >=75 Degarelix 240@40/80@20 96.6%87.0; 99.1% 78 Degarelix 240/160@40 94.5% 85.9; 97.9% 82 LUPRON DEPOT ®7.5 mg 86.8% 77.4; 92.5% 92 Log-rank test: Degarelix 240@40/80@20 vs.  p= 0.0376. LUPRON DEPOT ® 7.5 mg Degarelix 240/160@40 vs. p = 0.1125LUPRON DEPOT ® 7.5 mg Note: P values as flagging device used only in thePhase 3 study (head to head comparison to LUPRON DEPOT 7.5 mg), * = 0.01< P ≤ 0.05, ** = 0.001 < P ≤ 0.01, *** = P ≤ 0.001 (Fisher exact,two-sided).

PSA percent change from baseline is more pronounced in the patients withmetastatic stage prostate cancer (See Table 10 below). All subgroups arestatistically significantly better than LUPRON DEPOT® 7.5 mg.

TABLE 10 Effect of starting dose on PSA during first month of treatmentfor Controlled Study CS21-by stage of prostate cancer subgroups Day 14percentage change Day 28 percentage change in PSA in PSA MedianInterQuartile Median InterQuartile Day 0 dose % Range N % Range N PCA =Localized Degarelix −50.6% −65.0;−30.4%  128 −75.0% −85.2;−60.5% 128240@40 LUPRON −13.2% −29.3;−0.518% 63 −55.7% −66.7;−33.8% 63 DEPOT ® 7.5mg Wilcoxon rank sum test: Degarelix p = <.0001 p = <.0001 240@40 vs.LUPRON DEPOT ® 7.5 mg PCA-Locally advanced Degarelix −66.6% −75.9;−49.6%126 −84.1% −91.8;−75.0% 126 240@40 LUPRON −21.3% −36.2;−9.20% 52 −73.2%−84.0;−50.0% 52 DEPOT ® 7.5 mg Wilcoxon rank sum test: Degarelix p =.0001 p = <.0001 240@40 vs. LUPRON DEPOT ® 7.5 mg PCA = MetastaticDegarelix −77.9% −85.3;−62.3%  78 −89.9% −95.6;−83.1% 78 240@40 LUPRON−25.3% −53.2;−0.943% 47 −79.7% −90.6;−70.7% 47 DEPOT ® 7.5 mg Wilcoxonrank sum test: Degarelix p = <.0001 p = 0.0003 240@40 vs. LUPRON DEPOT ®7.5 mg Note: P values as flagging device used only in the Phase 3 study(head to head comparison to LUPRON DEPOT 7.5 mg), ^(*) = 0.01 < P ≤0.05, ^(**) = 0.001 < P ≤ 0.01, ^(***) = P ≤ 0.001(Fisher exact,two-sided).

Notable statistically significant findings in the total trial populationare (See Table 11):

Myocardial Infarction (PT): 0.5% (2/409, degarelix combined) versus 2.5%(5/201, LUPRON DEPOT® 7.5 mg),

Oedema peripheral (PT) 2% (8/409, degarelix combined) versus 5% (10/201,LUPRON DEPOT® 7.5 mg),

Chest pain: 0.5% (2/409, degarelix combined) versus 3% (6/201, LUPRONDEPOT® 7.5 mg),

Urinary Tract infection (PT) 3% (13/409, degarelix combined) versus 9%(18/201, LUPRON DEPOT® 7.5 mg),

Cardiac murmur (PT): 0% (0/409, degarelix combined) versus 1.5% (3/201,LUPRON DEPOT®7.5 mg),

Musculoskeletal and connective tissue disorders (SOC): 17% (68/409,degarelix combined) versus 26% (53/201, LUPRON DEPOT® 7.5 mg),

Arthralgia (PT within Musculoskeletal and CTD SOC): 4.2% (17/409,degarelix combined) versus 9% (18/201, LUPRON DEPOT® 7.5 mg),

Musculoskeletal stiffness (PT within Musculoskeletal and CTD SOC): 0%(0/409, degarelix combined) versus 1% (3/201, LUPRON DEPOT® 7.5 mg),

Libido decreased: 0% (0/409, degarelix combined) versus 1.5% (3/201,LUPRON DEPOT®7.5 mg),

Urinary retention: 1.2% (5/409, degarelix combined) versus 4.5% (9/201,LUPRON DEPOT®7.5 mg),

Cystitis noninfective: 0% (0/409, degarelix combined) versus 2% (4/201,LUPRON DEPOT®7.5 mg),

Erectile dysfunction: 1.5% (6/409, degarelix combined) versus 4.5%(9/201, LUPRON DEPOT®7.5 mg),

DVT: 0% (0/409, degarelix combined) versus 1.5% (3/201, LUPRON DEPOT®7.5 mg).

Particularly notable statistically significant findings in and acrosssubgroups are indicated.

TABLE 11 Crude Incidence of Treatment-Emergent Adverse Events by MedDRASystem Organ Class and Preferred Term One-Month Controlled LUPRONDEPOT ® MedDRA System Organ Class/Preferred Degarelix 7.5 mg Term N (%)N (%) Exposed Subjects 409 (100%) 201 (100%) Total No. of Subjects withAdverse 330 (81%) 156 (78%) Events BLOOD AND LYMPHATIC SYSTEM 16 (4%) 12(6%) DISORDERS Myocardial ischaemia 2 (<1%)* 5 (2%)* GENERAL DISORDERSAND ADMINISTRATION SITE CONDITIONS Oedema peripheral 8 (2%)* 10 (5%)*Chest pain 2 (<1%)* 6 (3%)* INFECTIONS AND INFESTATIONS Urinary tractinfection 13 (3%)** 18 (9%)** INVESTIGATIONS 113 (28%) 62 (31%) Cardiacmurmur 3 (1%)* MUSCULOSKELETAL AND 68 (17%)** 53 (26%)** CONNECTIVETISSUE DISORDERS Arthralgia 17 (4%)* 18 (9%)* Musculoskeletal stiffness3 (1%)* PSYCHIATRIC DISORDERS Libido decreased 0 3 (1%)* RENAL ANDURINARY DISORDERS Urinary retention 5 (1%)* 9 (4%)* Cystitisnoninfective 4 (2%)* REPRODUCTIVE SYSTEM AND 22 (5%)* 21 (10%)* BREASTDISORDERS Erectile dysfunction 6 (1%)* 9 (4%)* VASCULAR DISORDERS Deepvein thrombosis 0 3 (1%)* Note: P values as flagging device used only inthe Phase 3 study (head to head comparison to LUPRON DEPOT 7.5 mg), * =0.01 < P ≤ 0.05, ** = 0.001 < P ≤ 0.01, *** = P ≤ 0.001(Fisher exact,two-sided).

Musculoskeletal and connective tissue disorders (SOC) and Arthralgiasuperiority is not just confined to the metastatic, but in all diseasestage subgroup (see Table H=Table 2.2). Arthralgia is statisticallysignificant in locally advanced patients.

TABLE 12 Crude Incidence of Treatment-Emergent Adverse Events by MedDRASystem Organ Class and Preferred Term—by Stage of Prostate CancerOne-Month Controlled LUPRON DEPOT ® MedDRA System Organ Degarelix 7.5 mgClass/Preferred Term N (%) N (%) PCA = Localised Exposed Subjects 128(100%) 63 (100%) Total No. of Subjects with Adverse 104 (81%) 48 (76%)Events GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Oedemaperipheral 2 (2%)* 6 (10%)* INFECTIONS AND INFESTATIONS 22 (17%) 14(22%) Urinary tract infection 2 (2%)* 5 (8%)* Upper respiratory tractinfection 4 (3%) 6 (10%) MUSCULOSKELETAL AND 20 (16%) 16 (25%)CONNECTIVE TISSUE DISORDERS NEOPLASMS BENIGN, MALIGNANT 4 (3%) 6 (10%)AND UNSPECIFIED (INCL CYSTS AND POLYPS) PSYCHIATRIC DISORDERS 11 (9%) 9(14%) Depression 1 (<1%)* 4 (6%)* Libido decreased 2 (3%) REPRODUCTIVESYSTEM AND 5 (4%) 7 (11%) BREAST DISORDERS Gynaecomastia 1 (<1%) 2 (3%)Erectile dysfunction 1 (<1%)* 4 (6%)* PCA = Locally advanced ExposedSubjects 126 (100%) 52 (100%) Total No. of Subjects with Adverse 93(74%) 37 (71%) Events CARDIAC DISORDERS 4 (3%) 5 (10%) Atrioventricularblock first 3 (6%)* degree GASTROINTESTINAL DISORDERS 16 (13%) 11 (21%)Diarrhoea 1 (<1%)* 4 (8%)* INFECTIONS AND INFESTATIONS 16 (13%) 11 (21%)Urinary tract infection 1 (<1%)** 5 (10%)** INJURY, POISONING AND 2(2%)** 6 (12%)** PROCEDURAL COMPLICATIONS Fall 1 (<1%) 1 ( 2%)Excoriation 2 ( 4%) Muscle strain 1 (<1%) MUSCULOSKELETAL AND 13 (10%)10 (19%) CONNECTIVE TISSUE DISORDERS Back pain 6 ( 5%) 4 ( 8%)Arthralgia 2 (2%)** 7 (13%)** RESPIRATORY, THORACIC AND 9 ( 7%) 5 (10%)MEDIASTINAL DISORDERS Dyspnoea 0 3 (6%)* PCA = Metastatic ExposedSubjects 78 (100%) 47 (100%) Total No. of Subjects with Adverse 63 (81%)39 (83%) Events GASTROINTESTINAL DISORDERS 12 (15%) 12 (26%)MUSCULOSKELETAL AND 16 (21%) 17 (36%) CONNECTIVE TISSUE DISORDERS Backpain 4 ( 5%) 6 (13%) Arthralgia 4 ( 5%) 6 (13%) Pain in extremity 1 (1%) 4 ( 9%) Note: P values as flagging device used only in the Phase 3study (head to head comparison to LUPRON DEPOT 7.5 mg), * = 0.01 < P ≤0.05, ** = 0.001 < P ≤ 0.01, *** = P ≤ 0.001 (Fisher exact, two-sided).

Renal And Urinary Disorders and Musculoskeletal and Connective Tissuedisorders in Age <65 group (see Table 13)

TABLE 13 Crude Incidence of Treatment-Emergent Adverse Events by MedDRASystem Organ Class and Preferred Term—in the age <65 subgroup Age(years) = <65 One-Month Controlled LUPRON DEPOT ® MedDRA System OrganClass/ Degarelix 7.5 mg Preferred Term N (%) N (%) Exposed Subjects 80(100%) 38 (100%) Total No. of Subjects with Adverse 60 (75%) 31 (82%)Events GASTROINTESTINAL DISORDERS 7 (9%)* 9 (24%)* INFECTIONS ANDINFESTATIONS 13 (16%) 10 (26%) MUSCULOSKELETAL AND 7 (9%)** 13 (34%)**CONNECTIVE TISSUE DISORDERS Arthralgia 5 (13%)** RENAL AND URINARYDISORDERS 8 (10%)* 11 (29%)* Urinary retention 1 (1%)* 5 (13%)* Note: Nofindings in the other age-categories Note: P values as flagging deviceused only in the Phase 3 study (head to head comparison to LUPRON DEPOT7.5 mg), * = 0.01 < P ≤ 0.05, ** = 0.001 < P ≤ 0.01, *** = P ≤ 0.001(Fisher exact, two-sided).

See Table 14 and Table 15 for further subgroup findings.

TABLE 14 Crude Incidence of Treatment-Emergent Adverse Events by MedDRASystem Organ Class and Preferred Term—by Body Weight categoriesOne-Month Controlled LUPRON DEPOT ® MedDRA System Organ Class/PreferredDegarelix 7.5 mg Term N (%) N (%) Weight (kg) = <70 Exposed Subjects 102(100%) 39 (100%) Total No. of Subjects with Adverse 80 (78%) 30 (77%)Events MUSCULOSKELETAL AND 17 (17%)* 14 (36%)* CONNECTIVE TISSUEDISORDERS Arthralgia 3 ( 3%)** 7 (18%)** REPRODUCTIVE SYSTEM AND 4 (4%)*7 (18%)* BREAST DISORDERS Pelvic pain 0 3 (8%)* Weight (kg) = 70-<90Exposed Subjects 227 (100%) 125 (100%) Total No. of Subjects withAdverse Events 183 (81%) 95 (76%) CARDIAC DISORDERS 12 ( 5%)* 16 (13%)*NERVOUS SYSTEM DISORDERS 27 (12%) 13 (10%) Syncope 3 (2%)* REPRODUCTIVESYSTEM AND 11 ( 5%) 10 ( 8%) BREAST DISORDERS Erectile dysfunction 2(<1%)* 7 (6%)* Weight (kg) = >=90 Exposed Subjects 80 (100%) 37 (100%)Total No. of Subjects with Adverse 67 (84%) 31 (84%) Events INFECTIONSAND INFESTATIONS 21 (26%) 12 (32%) Urinary tract infection 2 ( 3%)* 5(14%)* Bronchitis 3 ( 8%)* MUSCULOSKELETAL AND 12 (15%)* 12 (32%)*CONNECTIVE TISSUE DISORDERS Arthralgia 4 ( 5%) 4 (11%) Back pain 4 (5%)* 7 (19%)* NEOPLASMS BENIGN, MALIGNANT 1 (1%)* 4 (11%)* ANDUNSPECIFIED (INCL CYSTS AND POLYPS) Note: P values as flagging deviceused only in the Phase 3 study (head to head comparison to LUPRON DEPOT7.5 mg), * = 0.01 < P ≤ 0.05, ** = 0.001 < P ≤ 0.01, *** = P ≤ 0.001(Fisher exact, two-sided).

TABLE 15 Crude Incidence of Treatment-Emergent Adverse Events by MedDRASystem Organ Class and Preferred Term—by Race One-Month ControlledLUPRON DEPOT ® MedDRA System Organ Class/ Degarelix 7.5 mg PreferredTerm N (%) N (%) Race = White Exposed Subjects 339 (100%) 172 (100%)Total No. of Subjects with Adverse 267 (79%) 131 (76%) Events CARDIACDISORDERS 33 (10%) 25 (15%) Myocardial ischaemia 2 (<1%)* 5 ( 3%)*GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Oedema peripheral 5(1%)* 10 (6%)* Chest pain 2 (<1%)* 5 ( 3%)* INFECTIONS AND INFESTATIONS64 (19%) 39 (23%) Upper respiratory tract infection 3 (<1%)* 7 (4%)*INVESTIGATIONS 88 (26%) 52 (30%) Cardiac murmur 3 (2%)* MUSCULOSKELETALAND 52 (15%)** 44 (26%)** CONNECTIVE TISSUE DISORDERS Musculoskeletalstiffness 0 3 (2%)* RENAL AND URINARY DISORDERS 46 (14%) 34 (20%)Urinary retention 4 ( 1%)* 7 (4%)* RENAL AND URINARY DISORDERS (cont.)Cystitis noninfective 0 4 (2%)* VASCULAR DISORDERS 106 (31%) 52 (30%)Orthostatic hypotension 0 3 (2%)* Deep vein thrombosis 0 3 (2%)* Race =Other Exposed Subjects 42 (100%) 19 (100%) Total No. of Subjects withAdverse 40 (95%) 16 (84%) Events INFECTIONS AND INFESTATIONS 14 (33%) 7(37%) Urinary tract infection 2 (5%)* 5 (26%)* REPRODUCTIVE SYSTEM AND 4(10%) 5 (26%) BREAST DISORDERS Erectile dysfunction 1 (2%)* 4 (21%)*Note: no findings in Blacks Note: P values as flagging device used onlyin the Phase 3 study (head to head comparison to LUPRON DEPOT 7.5 mg), *= 0.01 < P ≤ 0.05, ** = 0.001 < P ≤ 0.01, *** = P ≤ 0.001 (Fisher exact,two-sided).

These results shown in Tables 16 and 17 below demonstrate that treatedsubjects had a significantly reduced risk of developing coronary arterydisease, heart failure, myocardial infarction, cardiac arrhythmia,coronary artery disease or heart failure when receiving androgendepletion therapy with degarelix as compared to Lupron.

TABLE 16 Incidence Rate (in 1,000 py) of Cardiovascular Events comparedto Background Incidence Rates Degarelix LUPRON DEPOT ® 7.5 mg Inci-Inci- N dence 95% N dence 95% (%) PY Rate Cl (%) PY Rate Cl CV 3 0.3548.49 [1.75; 1 0.178 5.63 [0.142; P = 1.0 Event (<1%) 24.8] (<1%) 31.4]type Stroke Coronary 12 0.351 34.2 [17.7; 11 0.174 63.4 [31.6; P = 0.2artery (3%) 59.7] (5%) 113] disease Heart 5 0.354 14.1 [4.59; 5 0.17628.4 [9.21; P = 0.42 failure (1%) 33.0] (2%) 66.2] MI 2 0.354 5.64[0.683; 4 0.177 22.6 [6.15; P = 0.2 (<1%) 20.4] (2%) 57.8] Note: Pvalues as flagging device used only in the Phase 3 study (head to headcomparison to LUPRON DEPOT 7.5 mg), ^(*) = 0.01 < P ≤ 0.05, ^(**) =0.001 < P ≤ 0.01, ^(***) = P ≤ 0.001 (Fisher exact, two-sided).

TABLE 17 Incidence Rate of Cardiovascular Events defined by High LevelGroup Terms Degarelix LUPRON DEPOT ® 7.5 mg Inci- Inci- dence dence N(%) PY Rate 95% Cl N (%) PY Rate 95% Cl MedDRA HLGT Central nervous 50.353 14.2 [4.60; 1 0.178 5.63 [0.142; P = system (<1%) 33.1] (<1%)31.4] 0.69 vascular disorders Cardiac 20 0.347 57.7 [35.3; 17 0.170 100[58.2; P = arrhythmias (5%) 89.1] (8%) 160] 0.13 Coronary 12 0.351 34.2[17.7; 11 0.174 63.4 [31.6; P = artery disorders (3%) 59.7] (5%) 113]0.21 Heart failures 5 0.354 14.1 [4.59; 5 0.176 28.4 [9.21; P = (<1%)33.0] (2%) 66.2] 0.42 Note: P values as flagging device used only in hePhase 3 study (head to head comparison to LUPRON DEPOT 7.5 mg), ^(*) =0.01 < P ≤ 0.05, ^(**) = 0.001 < P ≤ 0.01, ^(***) = P 0.001 ≤ (Fisherexact, two-sided).

Mortality Subgroups with Statistically (Pre-Planned as Part of the ISS)Significant Findings

TABLE 18 Mortality by Treatment group Age (years) = >=65-<75 Mortalityper 1,000 PY Treatment No. of Crude PY of 95% Group N Deaths MortalityExposure Estimate Cl Degarelix 169 3 (2%) 0.148 20.2 [4.17; 59.1] LUPRON71 6 (8%) 0.061 99.0 [36.3; DEPOT ® 216] 7.5 mg Test for P = homogeneity0.0426 of mortality rates:

TABLE 19 Mortality by Treatment group PCA = Localized Mortality per1,000 PY Treatment No. of Crude PY of 95% Group N Deaths MortalityExposure Estimate Cl Degarelix 128 0 (0%) 0.113 0 [0, 32.6] LUPRON 63 4(6%) 0.057 70.3 [19.2; DEPOT ® 180] 7.5 mg Test for P = homogeneity of0.025 mortality rates: 1

TABLE 20 Incidence rates ratios by BMI of Cardiac Arrhythmias inCS21-Degarelix vs Luprolide Degarelix Lupron Relative Risk Body MassInci- Inci- P Index dence 95% dence 95% 95% value Category Rate CI RateCI RR CI (a) 1: <25 kg/m2 46.58 (17.1- 149.3 (64.4- 0.312 (0.09- .0556101) 294) 1.03) 2: 25-<30 kg/m2 52.66 (24.1- 93.09 (40.2- 0.566 (0.19-.3495 100) 183) 1.68) 3: >= 30 kg/m2 84.50 (27.4- 26.73 (0.68- 3.161(0.35- .5069 197) 149) 150) (a) P value for for homogeneity of incidencerates PY in 1,000 person years

These results show that treated subjects with BMIs of less than 30 kg/m²(e.g., less than 25 kg/m², e.g., 20-25 kg/m²) had a significantlyreduced risk of developing a cardiac arrhythmia when receiving androgendepletion therapy with degarelix as compared to Lupron.

TABLE 21 Incidence rates ratios by BMI of Coronary Artery Disorders inCS21-Degarelix vs Luprolide Body Degarelix Lupron Relative Risk MassInci- Inci- P Index dence 95% dence 95% 95% value Category Rate CI RateCI RR CI (a) 1: <25 0.00 (0.00- 87.96 (28.6- 0.000 (0.00- 0.0050 kg/m228.0) 205) 0.47) 2: 25-<30 46.88 (20.2- 46.27 (12.6- 1.013 (0.27- 1.000kg/m2 92.4) 118) 4.60) 3: >=30 65.16 (17.8- 53.53 (6.48- 1.217 (0.17-1.000 kg/m2 167) 193) 13.5) (a) P value for homogeneity of incidencerates PY in 1,000 person years

These results show that treated subjects with BMIs of less than 25 kg/m²(e.g., 20-25 kg/m²) had a significantly reduced risk of developing acoronary artery disorder when receiving androgen depletion therapy withdegarelix as compared to Lupron.

TABLE 22 Incidence rates ratios by BMI of Cardiac Disorders (SOC) inCS21-Degarelix vs Luprolide Body Degarelix Lupron Relative Risk MassInci- Inci- P Index dence 95% dence 95% 95% value Category Rate CI RateCI RR CI (a) 1: <25 54.32 (21.8- 224.9 (116- 0.242 (0.08- .0045 kg/m2112) 393) 0.67) 2: 25-<30 101.5 (59.1- 132.6 (66.2- 0.765 (0.34- .6106kg/m2 162) 237) 1.81) 3: >= 30 209.6 ( 108- 107.7 (29.4- 1.946 (0.59-.3606 kg/m2 366) 276) 8.28) (a) P value for for homogeneity of incidencerates PY in 1,000 person years

These results show that treated subjects with BMIs of less than 30 kg/m²(e.g., less than 25 kg/m², e.g. 20-25 kg/m²) had a significantly reducedrisk of developing a cardiac disorder when receiving androgen depletiontherapy with degarelix as compared to Lupron.

TABLE 23 Incidence rates ratios by Cholesterol of Cardiac Arrhythmias inCS21-Degarelix vs Luprolide Degarelix Lupron Relative Risk Inci- Inci- PCholesterol dence 95% dence 95% 95% value Category Rate Cl Rate Cl RR Cl(a) 1: <4 156.1 (62.8- 79.12 (16.3- 1.973 (0.45- .4981 mmol/L 322) 231)11.8) 2: >= 4 41.39 (22.0- 100.7 (55.1- 0.411 (0.18- .0350 mmol/L 70.8)169) 0.94) (a) P value for homogeneity of incidence rates PY in 1,000person years

These results show that treated subjects with cholesterol levels ofgreater than or equal to 4 mmol/L had a significantly reduced risk ofdeveloping a cardiac arrhythmia when receiving androgen depletiontherapy with degarelix as compared to GnRH antagonist therapy withLupron.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described herein. Such equivalents are intended tobe encompassed in the scope of the following claims.

Example 2: Clinical Study Comparing Cardiovascular Event Rates UsingGnRH Antagonist Versus Agonist

In this example, a study was conducted to investigate the risk ofcardiovascular events when ADT is utilized by a GnRH antagonist versusagonist in patients with or without a history of cardiovascular events.

Specifically, this study utilized available data yielding a safetydatabase of 2328 PCa (prostate cancer) patients who participated inrandomized clinical trials and received treatment with either degarelixor a GnRH agonist for up to 12 months (13 treatment months).Justification for performing the comparison over this relatively shorttreatment period comes from numerous observations indicating that theincreased risk of cardiovascular (CV) morbidities associated with theuse of GnRH agonists was detectable during the first 12 months oftreatment (Saigal et al. (2007) Cancer 110:1493-500) and as early asafter 1-4-month (Keating et al. (2006) J. Clin. Oncol. 24:4448-56) or6-month (D'Amico et al. (2007) J. Clin. Oncol. 25:2420-2425) exposure.

Study Design

The study is based on data from two completed Phase 3 and 4 Phase 3btrials, all of which used an active comparator in form of a GnRHagonist. In each study, the primary inclusion criteria were malesubjects ≥8 years of age with histologically confirmed adenocarcinoma ofthe prostate in whom ADT was indicated and a life expectancy of minimum12 months could be anticipated. All subjects had serum testosteronelevels that were either within the age-specified normal range or abovethe lower limit of the normal range of the central laboratory and ECOGscore ≤2. Exclusion criterion ensured that none of the subjects hadreceived long-term ADT (>6 months) before study entry. The number ofpatients and drug doses utilized for each trial are summarized in FIG. 7.

The clinical trials were performed in accordance with the Declaration ofHelsinki and Good Clinical Practice guidelines. The respective studyprotocols were approved by independent Ethics Committees andInstitutional Review Boards.

Baseline evaluation included thorough collection of the main demographiccharacteristics (age, weight, height), lifestyle factors (smoking anddrinking habits), and major CV risk factors (treated type 2 diabetes,treated hyperlipidemia, treated hypertension, and systolic and diastolicblood pressure). Patients also underwent physical examination and ECGassessment for potential cardiac morbidities. Medical history of CVevents was captured by the following Standardized MedDRA Queries(myocardial infarction, ischemic heart diseases, ischemic stroke,hemorrhagic stroke, other arterial thrombotic/embolic events).

Serum testosterone was typically measured at baseline and then monthlyin all cases. Serum testosterone was measured at a central laboratoryusing a validated liquid chromatography system with a tandem massspectrometry assay with a lower limit of quantitation of 3 ng/dl.

Cardiovascular events of interest were collected prospectively,typically at monthly visits, as adverse events or serious adverse eventswith date of occurrence. These events were coded using standard MedDRAterms and grouped into one of the same categories as those used tocollect medical history.

Statistical Methods

The CV event rates in agonist and antagonist-treated patients wereanalyzed by 1-Kaplan-Meier plots of time to first-reported CV events andcompared with log-rank test. The analysis was performed separately forstrata of patients with or without history of CV events. To identifyindependent predictors of CV events we applied multivariate Coxproportional hazards models. All analyses were done at the 5% nominalsignificance level using SAS®, version 9.2.

Results

Baseline characteristics of the population stratified according totreatment received are outlined in Table 24. Reflecting the fact thatthe data come from randomized clinical trials, patient characteristicswere balanced throughout the parameters listed. History of CV events wasreported by approximately one third of the patients in both treatmentarms.

TABLE 24 Baseline characteristics of prostate cancer patients stratifiedaccording to received treatment. DEGARELIX AGONIST N = 1491 N = 837 Age,years (SD) 71.7 (8.1) 71.6 (8.1) BMI, kg/m² (SD) 27.2 (4.4) 27.5 (4.4)BMI kg/m² 22.4% 23.9% Serum testosterone (ng/ml)  4.32 (1.84)  4.36(1.78) Regular alcohol consumption, yes % 56.3%   54% Ever smoking, yes% 48.6% 52.2% Heart rate, beat per minute (SD)  71 (11)  71 (11)Systolic blood pressure, mmHg (SD) 137 (17) 137 (16) Diastolic bloodpressure, mmHg (SD)  79 (10)  79 (10) Systolic blood pressure >140 mmHgor   33%   33% Diastolic blood pressure >90 mmHg Treated hypertension,yes % 27.9% 28.4% Treated hyperlipidemia, yes % 26.8% 27.8% Treated type2 diabetes, yes % 11.9% 11.2% History of CV event *, yes % * 31.1% 33.7%Prostata cancer stage Localized 34.4% 34.3% Locally advanced 25.8% 22.2%Metastatic 18.9% 18.4% Non-classifiable 20.9% 25.1%

Median exposure to the antagonist or the agonists was 11.96 treatmentmonths. Short-term exposure <7 months was received by one third of thepatients (agonist 242 [28.9%]; degarelix: 417 [28.0%]), whereas >7months exposure was received by two third (agonist: 595 [71.1%],degarelix: 1074 [72.0%]).

Median testosterone levels monitored on a monthly basis throughout therespective treatment periods are outlined in FIG. 8 . From Day 28 (Month1), testosterone was suppressed to comparable levels (below castrationlevel <0.5 ng/ml) in all clinical trials by both the agonist anddegarelix.

During the treatment period, 81 patients reported at least one CV event.For 39 patients, this was already a secondary event (i.e., an additionalcardiovascular event), whereas for 42 patients it was a primary event.By these 81 patients, a total of 153 CV events were reported reflectingthat one patient could report several events at a time and/or during thecourse of the treatment. Details on the type of CV events and theirdistribution between treatment arms are listed in Table 25.

TABLE 25 Frequency of various cardiovascular events per treatment armDEGARELIX AGONIST N = 1491 N = 837 N % E % N % E % Any CV 44 2.9% 906.0% 37 4.4% 63 7.5% adverse event Myocardial 13 0.8% 15 1.0% 11 1.3% 111.3% infarction Ischemic 25 1.7% 27 1.8% 17 2.0% 18 2.2% heart diseaseIschemic 14 0.9% 16 1.1% 10 1.2% 10 1.2% stroke Hemorrhagic 3 0.2% 30.2% 5 0.6% 5 0.6% stroke Other 23 1.5% 29 1.9% 17 2.0% 19 2.3% embolicor thrombotic events, arterial N = Number of patients with adverseevents E = Number of adverse events

Event Rates in Patients with or without History of CV Events

When comparing 1-Kaplan-Meier plots of time to first-reported CV eventin degarelix versus agonist treated patients with no history of CVevents, the plots were very similar throughout the observation period(FIG. 9A). Corresponding event rates were 6.4 and 4.1 events per 100Person-year (p=0.11). In contrast, when comparing the plots obtainedfrom patients with a history of CV events (i.e., at least one CV event),there was a significantly higher rate of CV events in agonist (22.4event per 100 Person-year) versus degarelix-treated patients (11.3 eventper 100 Person-year, p=0.0015) (FIG. 9B). Similar trends were observedwhen focusing on monthly treatment regimes only (FIGS. 9C and 9D).

Adjustment for age and PCa stage (metastatic vs. others) did not changethe separation of the curve (HR=0.49, 95% CI 0.32-0.74, p=0.0009).

Independent Predictors of CV Events

To further explore the apparent independent role of treatment choice andidentify independent modifiable risk factors, this study established Coxproportional hazard models including CV events occurring duringtreatment as dependent variable and age, history of CV event, drinking(i.e., high alcohol consumption or abstinence) and smoking habits,hypertension, serum testosterone level and PCa disease stage asindependent variables.

As expected, the highest risk was posed by history of a CV event markingadvanced vascular disease (2.23-fold).

Other risk factors included age, abstinence to alcohol, high bloodpressure (regardless of treatment), and low baseline serum testosterone.Although smoking and metastatic disease stage was associated withincreased hazard rates (HRs), these factors did not reach statisticalsignificance.

When taking into consideration all of these characteristics and CV riskfactors, the risk of an event was 38% lower if taking degarelix versusthe agonist (HR=0.62, 95% CI 0.39-0.97, p=0.037).

Analysis

One finding from this study was the ˜2-fold higher CV event rate inagonist versus antagonist-treated patients with a history of CV events(i.e., at least one cardiovascular event) in face of comparable eventrates in patients with no CV history. The observation that advancedvascular disease is a prerequisite of the apparent harm of agonistsimplicates destabilization of existing atherosclerotic plaques as theplausible mechanism, which is affected reciprocally by the two drugclasses.

The finding that the relative increase in the risk of CV events posed byagonists regards patients with advanced CV disease finds link tonumerous epidemiological studies documenting the association of GnRHagonists to CV harm in older patients, i.e. ≥66 years old (Keating etal. (2006) J. Clin. Oncol. 24:4448-56; and Saigal et al. (2007) Cancer110:1493-500). It was the study by Tsai et al ((2007) Natl. Cancer Inst.99:1516-24) that highlighted by stratified analysis that the excess inCV risk posed by GnRH agonists is higher in patients >65 years than intheir younger counterparts. Since the prevalence and severity ofatherosclerosis is increasing with advancing age (Wong et al. (2011)Atherosclerosis 214:436-41), it is reasonable to assume that populationsof elderly are likely enriched for patients with advancedatherosclerosis, which in turn can increase susceptibility tocomplications. This line of thinking was directly supported byobservations highlighting increased all-cause mortality in patients witha history of a major CV event (Hayes et al. (2010) 106:979-85; andD'Amico et al. (2008) JAMA 299:289-95).

Randomized clinical trials can be particularly useful to dissect theindependent contribution of medications to CV risk. These trials yieldbalanced treatment arms, collect detailed data on medical history andbaseline risk factors, and monitor patients closely for safety data in aprospective manner. A recent meta-analysis of 8 randomized trialscollectively involving 4141 patients found no differences in theincidence of CV deaths between treatment arms with or without GnRHagonist treatment over a 10-year follow-up period (Nguyen et al. (2011)JAMA 306:2359-66). While this finding seemingly contradicts theepidemiological studies, there are numerous issues accompanying thisapproach.

For example, the very long follow-up time (7 to 13 years) introducessignificant contribution by aging and related metabolic alterations,which is among the strongest drivers of CV events. These factors may onthe long run overshadow drug-related risks, especially if they arise inthe early phase of the treatment, as suggested by numerous observations,and only in certain subpopulations. Furthermore, the meta-analysis didnot allow conducting time-to-event analysis and stratification accordingto underlying CV disease, hence leaving uncertainties to theirconclusions. These limitations were carefully highlighted by the authorsand they called upon further data from randomized clinical trials toinvestigate these pending issues.

The present analysis took these recommendations into account and addedan additional angle to it by using a unique control setting. Bycontrasting the GnRH agonists to a parallel group of patients treatedwith an antagonist it was also possible to address the direct role ofGnRH receptors independent of androgen deprivation that was comparablebetween treatment arms. The combined consideration of these conditionsrevealed clear differences between agonists and antagonists in terms oftheir CV harm. In the lack of a parallel untreated group of patientswith history of CV events, there is no direct evidence that CV eventrate in the degarelix treatment arm is comparable with what can beexpected from patients with a history of CV disease. However, it isunlikely that the GnRH antagonist—having no possibility by moleculardesign to evoke signal transduction—can trigger events via GnRHreceptors (Beckers et al. (1997) Anal. Biochem. 251:17-23). Moreover,the herein argued scenarios could also help to explain theinconsistencies between previous studies by emphasizing the relativeimportance of patients with history of major CV events in the studypopulation. Low percentage of patients with a history of CV event coulddrive negative, whereas high percentage of patients with CV historycould drive positive overall conclusions.

There is no definitive understanding as to how differences in themodulation of GnRH receptors by the two drug classes could differentiateCV safety profiles. The differences in the action of these drugs are tobe found outside the pituitary gland that merely drives the suppressionof testicular testosterone production, an effect that is comparablebetween agonists and antagonists beyond 14-28 days (Klotz et al. (2008)BJU Int. 102:1531-8). Demonstration of the presence of functionallyactive GnRH receptors in lymphocytes (Chen et al. (1999) J. Clin.Endocrinol Metab. 84:743-50; Tanriverdi et al. (2004) Exp. Clin.Endocrinol Diabetes 112:587-94; and Tanriverdi et al. (2005) Clin. Exp.Immunol. 142:103-10), a player in the immuno-inflammatory system hasopened new avenues for the exploration of differences in the systemicpharmacodynamic effects of agonists and antagonists. Since these cellsare present in late-stage atherosclerotic plaques and play a key role inthe regulation of collagen turnover and thereby the stability of theplaque (Businario et al. (2005) Ital. J. Anat. Embroyl 110(2 Suppl1):109-15; Abbate et al. (2008) Heart 94:737-42; and de Boer et al.(1999) J. Pathol. 188:174-9), due consideration and targetedinvestigations in future studies seem warranted.

The multivariate analyses highlighted numerous independent risk factorsfor CV events during ADT and thereby a constellation of characteristicsthat predispose to an event relatively shortly after treatmentinitiation. Patients with advanced age, history of CV event who arehaving low baseline testosterone (possibly reflecting central adiposityand concomitant risk of accelerated atherosclerosis), hypertension orpoorly controlled hypertension, and are abstinent to alcohol areseemingly at the highest risk for CV complications during ADT. Even inthese patients, choosing an antagonist versus an agonist could reducethe relative risk by ˜40%, which could theoretically be further improvedby targeted lifestyle modifications (blood pressure control, weightloss, and moderate alcohol consumption).

What is claimed is:
 1. A method of treating prostate cancer in asubject, comprising: selecting a subject that has prostate cancer and ahistory of at least one cardiovascular event; and administeringdegarelix to the subject, wherein administering degarelix to the subjectcomprises administering to the patient an initial dose of degarelix of240 mg given as two injections of 120 mg each, and administering to thepatient a maintenance dose of degarelix of 80 mg given as one injection,wherein the maintenance dose is administered approximately every 28 daysafter the previous dose of degarelix for a duration treatment, whereinadministering degarelix to the subject decreases the likelihood ofdeveloping or experiencing an additional cardiovascular event comparedto treatment with a gonadotrophin releasing hormone (GnRH) agonist. 2.The method of claim 1, wherein the at least one cardiovascular event ischosen from myocardial infarction, ischemic heart disease, ischemicstroke, hemorrhagic stroke, and other arterial thrombotic/embolicevents.
 3. The method of claim 1, wherein the subject has at least onerisk factor chosen from greater than 65 years of age, high alcoholconsumption, abstinence from alcohol, high blood pressure, low baselineserum testosterone, and prostate cancer disease state.
 4. The method ofclaim 3, wherein the high blood pressure is greater than or equal to 130over 85 mm Hg.
 5. The method of claim 1, wherein the prostate cancer ischosen from localized prostate cancer, locally advanced prostate cancer,metastatic prostate cancer, and non-classifiable prostate cancer.
 6. Themethod of claim 1, wherein the decreased likelihood of developing orexperiencing an additional cardiovascular event is chosen frommyocardial infarction or stroke.
 7. The method of claim 1, wherein theinitial dose of degarelix is given as two subcutaneous injections of 120mg each at a concentration of 40 mg/mL.
 8. The method of claim 1,wherein the maintenance dose of degarelix of 80 mg is given as onesubcutaneous injection at a concentration of 20 mg/mL.
 9. The method ofclaim 1, wherein the treatment with a GnRH agonist is treatment withmonthly intramuscular injections of 7.5 mg leuprolide.
 10. The method ofclaim 1, wherein the subject's risk of experiencing an increase in bodyweight is diminished compared to a risk of experiencing an increase inbody weight upon treatment with a GnRH agonist.
 11. The method of claim10, wherein the treatment with a GnRH agonist is treatment with monthlyintramuscular injections of 7.5 mg leuprolide.